IRE-1α inhibitors

ABSTRACT

Compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts thereof. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response or with regulated IRE1-dependent decay (RIDD) and can be used as single agents or in combination therapies.

Each patent, patent application, and reference cited in this disclosureis expressly incorporated herein by reference in its entirety.

This application incorporates by reference the contents of a 1.32 kbtext file created on Jan. 12, 2015 and named “sequencelisting.txt,”which is the sequence listing for this application.

FIELD OF THE INVENTION

The field of the invention includes IRE-1α inhibitors and theirtherapeutic uses.

BACKGROUND

Protein folding stress in the endoplasmic reticulum of a cell initiatesa signal transduction cascade termed the unfolded protein response orUPR. A key enzyme, inositol requiring enzyme 1 (IRE-1α), relievesprotein folding stress by enhancing molecular chaperone activity andtherefore protects cells from stress induced apoptosis. Inhibitors ofIRE-1α are useful for treating at least B cell autoimmune diseases,certain cancers, and some viral infections.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows inhibition of endogenous XBP-1 splicing in RPMI 8226 cellsusing 10 μM IRE-1α endoribonuclease inhibitor (Cmpd) and Thapsigargin(Tg) induced XBP-1s. PCR amplification products were run on a 4% agarosegel and stained with ethidium bromide. The inverse image is shown.

FIGS. 2A-C show inhibition of regulated IRE1-dependent decay (RIDD) ofBlos1 (FIG. 2A) and CD59 (FIG. 2B) in human RPMI 8226 cells using aselective IRE-1α endoribonuclease inhibitor. GAPDH (FIG. 2C) is shown asa control. Cells were left untreated or treated with 10 uM IRE-1αinhibitor or 300 nM thapsigargin (Tg) or both or for 2, 4, 6, 8, 16 or24 hours. Total RNA was harvested and RT-qPCR was performed usingspecific primers for each of the individual mRNAs. The expression levelsare shown as Ct values where one PCR cycle correlates to a 2-foldchange.

FIG. 3A. Time course of experiment described in Example 44.

FIG. 3B. Results of RT-PCR analysis performed using murine-specificXBP-1 primers from total RNA harvested from specified organs afterintraperitoneal treatment with an IRE-1α inhibitor (Example 44).

FIG. 4A. Results of RT-PCR analysis performed using murine-specificXBP-1 primers from total RNA harvested from specified organs afterintravenous treatment with an IRE-1α inhibitor (Example 44).

FIG. 4B. Results of RT-PCR analysis performed using murine-specificXBP-1 primers from total RNA harvested from specified organs after oraltreatment with an IRE-1α inhibitor (Example 44).

FIG. 5A. Time course of experiment described in Example 45.

FIG. 5B. Results of RT-PCR amplification of XBP-1 using human specificprimers.

FIG. 6A. Time course of experiment described in Example 46.

FIG. 6B. Results of RT-PCR amplification of XBP-1 using human specificprimers.

DETAILED DESCRIPTION

This specification describes IRE-1α inhibitor compounds and prodrugs andpharmaceutically acceptable salts thereof; purified preparations IRE-1αinhibitor compounds and prodrugs and pharmaceutically acceptable saltsthereof; pharmaceutical compositions comprising IRE-1α inhibitorcompounds and prodrugs and pharmaceutically acceptable salts thereof;and methods of using IRE-1α inhibitor compounds, prodrugs, andpharmaceutically acceptable salts thereof therapeutically to treatdisorders associated with the unfolded protein response. Patients whocan be treated include those with B cell autoimmune diseases, certaincancers, and some viral infections. In other embodiments IRE-1αinhibitor compounds, prodrugs, or pharmaceutically acceptable saltsthereof can be administered to treat disorders associated with regulatedIRE1-dependent decay (RIDD). Other embodiments are intermediates ofIRE-1α inhibitor compounds and methods of synthesizing IRE-1α inhibitorcompounds as set forth in the specific Examples, below.

DEFINITIONS

“Halogen” includes fluorine, chlorine, bromine, and iodine.

Unless otherwise specified, the term “alkyl” as used herein means asaturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6carbon atoms (“C1-C6 alkyl”) and can be linear, branched, or acombination thereof. “C1-C6 alkyl” includes C1-C5 alkyl, C1-C4 alkyl,and C1-C3 alkyl. Examples of C1-C6 alkyls include methyl, ethyl, propyl,isopropyl, sec-butyl, tert-butyl, n-butyl, 2-butyl, pentyl, and hexyl.

“Alkoxy” as used herein means —O— alkyl groups, where “alkyl” is asdefined above, and can be linear, branched, or a combination thereof.Examples of C1-C6 alkoxys include, for example, methoxy, ethoxy,propoxy, 2-propoxy, butoxy, sec-butoxy, and tert-butoxy.

The term “perfluoroalkyl” means an alkyl group as defined above in whichall of the hydrogen atoms are replaced by fluorine atoms. The term“perfluoroalkoxy” means an alkoxy group in which the alkyl moiety is aperfluoroalkyl group as defined above.

The term “hydroxylalkyl” as used herein means an alkyl group as definedabove which is substituted with a hydroxyl group.

The term “alkoxylalkyl” means radicals of the formulaC_(a)H_(2a+1)—O—(CH₂)_(b)—, in which a and b independently are 1, 2, 3,4, 5, or 6.

A “cycloalkyl” is a saturated or partially saturated 3- to 14-membered(i.e., a 3-, 4-, 5-, 6, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered)monocyclic or polycyclic ring, such as a 5-, 6-, or 7-memberedmonocyclic ring or a 10-membered bicyclic ring, in which all of the ringmembers are carbon atoms. Examples of cycloalkyls include cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

“Aryl,” when used alone or as part of another term, means a carbocyclicaromatic ring containing 5 to 14 members (e.g., 5, 6, 7, 8, 9, 10, 11,12, 13, or 14 members) and can be monocyclic or polycyclic. Examples ofaryls include phenyl, naphthyl, anthryl, and phenanthryl.

A “heterocycle,” “heterocyclic group,” and “heterocyclic ring” is asaturated or a partially saturated 4- to 14-membered (i.e., 4-, 5-, 6-,7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered) monocyclic or polycyclic(fused) ring, such as a 5-, 6-, or 7-membered monocyclic ring or a10-membered bicyclic ring which has 1, 2, 3, or 4 heteroatoms selectedfrom nitrogen (N), oxygen (O), and sulfur (S). Any of the nitrogen andsulfur heteroatoms optionally can be oxidized, and any nitrogenheteroatom optionally can be quaternized. A heterocyclic ring can beattached at any suitable heteroatom or carbon atom. Examples ofheterocycles include azepinyl, furyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl,isobenzofuranyl, furazanyl, indolyl, quinolinyl, oxazolyl, imidazolinyl,isoxazolyl, quinolyl, naphthyridinyl, phenoxazinyl, phenanthridinyl,chromenyl, triazinyl, purinyl, benzothienyl, benzimidazolyl,benzopyranyl, benzothiazolyl, benzoazolyl, benzo[b]thienyl,naphtho[2,3-b]-thienyl, isothiazolyl, thiazolyl, isothiazolyl,isoquinolinyl, thiadiazolyl, oxadiazolyl, tetrahydroquinolinyl,indolizinyl, isoindolyl, indazolyl, isoquinolyl, phthalazinyl,tetrahydroquinolinyl, and cinnolinyl.

A “heteroaryl” is a saturated 4- to 14-membered (i.e., 4-, 5-, 6-, 7-,8-, 9-, 10-, 11-, 12-, 13-, or 14-membered) monocyclic or polycyclic(fused) ring, such as a 5-, 6-, or 7-membered monocyclic ring or a10-membered bicyclic ring which has 1, 2, 3, or 4 heteroatoms selectedfrom nitrogen (N), oxygen (O), and sulfur (S). Any of the nitrogen andsulfur heteroatoms optionally can be oxidized, and any nitrogenheteroatom optionally can be quaternized. A heteroaryl can be attachedat any suitable heteroatom or carbon atom. Examples of heteroarylsinclude pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl,pyrimidinyl, pyridazinyl, indolyl, quinolyl, naphthyridinyl, andisoxazolyl.

IRE-1α Inhibitor Compounds

IRE-1α inhibitor compounds directly inhibit IRE-1α. The compounds areunderstood to act through inhibition of the RNAse activity of theenzyme. In some embodiments IRE-1α inhibitor compounds form a complexwith IRE-1α. In particular embodiments this activity is detected ascleavage of a human mini-XBP-1 mRNA stem-loop substrate5′-CAGUCCGCAGGACUG-3′ (SEQ ID NO:1) by IRE-1α in vitro by 10 to 100%.Other substrates also can be used to detect cleavage. See US2007/0105123.

IRE-1α inhibitor compounds can meet either or both of the followingcriteria:

-   -   a. Some compounds inhibit IRE-1α in the in vitro assay with an        IC₅₀ of approximately 0.0005-20 μM. Some of these compounds have        an IC₅₀ in this assay of approximately 1-20 μM. Others have an        IC₅₀ in this assay of approximately 0.1-1 μM. Still others have        an IC₅₀ of approximately 0.0005-0.1 μm.    -   b. Some compounds inhibit IRE-1α in an in vivo XBP-1 splicing        assay (e.g., in myeloma cells) with an EC₅₀ in the range of        approximately 0.05-80 μM. Some of these compounds have an EC0₅₀        in this assay of approximately 10-80 μM. Others have an EC0₅₀ in        this assay of approximately 1-10 μM. Still others have an EC0₅₀        in this assay of approximately 0.05-1 μM.

Compounds fall into one or more of the structural formulae describedbelow. Non-limiting examples of compounds falling within the scope ofthese structural formulae are provided in Tables 1 and 2 and in theExamples.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A):

wherein:

-   R3 and R4 independently are hydrogen; halogen; hydroxyl; optionally    substituted alkyl; or optionally substituted alkoxyl; or optionally    substituted alkylamino. Optional substituents for the alkyl or for    the alkoxyl and alkylamino are (1) a C1-C6 hydrocarbon chain    containing an N or O atom and optionally substituted with a C1-C3    perfluoroalkyl, and (2) a cycloalkyl which may contain 1 or 2    heteroatoms selected from N, O, and S, and which is optionally    substituted with a C1-C3 perfluoroalkyl;-   Q5, Q6, Q7 and Q8 (used throughout this specification    interchangeably with Q₅, Q₆, Q₇ and Q₈), together with the benzene    ring to which they are attached, form a benzofused ring. In some    embodiments, Q7 is a bond which connects Q6 and Q8. The benzofused    ring may or may not be fully aromatic.-   Q5 is CR5, CR5R5′, N, NR5, NC═OR5, O, S, or C═O;-   Q6 is CR6, CR6R6′, N, NR6, NC═OR6, O, S, or C═O;-   Q7 is CR7, CR7R7′, N, NR7, NC═OR7, O, S, C═O, or a bond; and-   Q8 is CR8, CR8R8′, N, NR8, NC═OR8, O, S, C═O,    -   PROVIDED THAT: at least one of Q5, Q6, Q7 (when not a bond), and        Q8 must be a heteroatom selected from N, S, and O and Q5, Q6,        Q7, and Q8 do not form O—O, O—N, O—S, or O═C—C═O bonds.-   R5, R5′, R6, R6′, R7, R7′, R8, and R8′ are independently hydrogen;    R21;

alkenyl, alkynyl, or phenyl, each optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl,

-   -   PROVIDED THAT:        -   1. R5, R5′, R6, R6′, R7, R7′, R8, and R8′ are not            simultaneously hydrogen;        -   2. when R5, R5′, R6, R6′, R7, R7′, R8, and R8′ are            independently

-   -    none of Q5, Q6, Q7, and Q8 is N, O, or S; and        -   3. when R5, R5′, R6, R6′, R7, R7′, R8, and R8′ are            independently a 5- or 6-membered heteroaryl substituted with            1, 2, or 3 substituents independently selected from

then the

is linked to a carbon atom of the 5- or 6-membered heteroaryl;

-   R9 and R10 are independently hydrogen; alkyl; alkoxylalkyl;    perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3    substituents independently selected from R21; a 5- or 6-membered    heterocycle, optionally substituted with 1, 2, or 3 substituents    independently selected from R21; a 5- or 6-membered heteroaryl,    optionally substituted with 1, 2, or 3 substituents independently    selected from R21; or

wherein n is 0, 1, 2, or 3; or

-   R9 and R10, together with the nitrogen atom to which they are    attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms    selected from N, O, and S, optionally substituted with 1, 2, or 3    substituents selected independently from R11;-   R11 is hydrogen; alkyl; aryl; heteroaryl containing 1 or 2    heteroatoms selected from N, O, and S; arylalkyl; heteroarylalkyl in    which the heteroaryl contains 1 or 2 heteroatoms selected from N, O,    and S;

-   R12 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3    substituents selected independently from R11; a 5- or 6-membered    heterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S    and optionally substituted with 1, 2, or 3 substituents selected    independently from R11; or a 5- or 6-membered heteroaryl having 1,    2, or 3 heteroatoms selected from N, O, and S and optionally    substituted with 1, 2, or 3 substituents selected independently from    R11;-   R13 is alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally    substituted with 1, 2, or 3 substituents independently selected from    R21; a 5- or 6-membered heterocycle, optionally substituted with 1,    2, or 3 substituents independently selected from R21; a 5- or    6-membered heteroaryl, optionally substituted with 1, 2, or 3    substituents independently selected from R21; or

wherein n is 0, 1, 2, or 3; and R14 is hydrogen or R13; or

-   R13 and R14, together with the nitrogen to which they are attached,    form a heterocycle containing 1, 2, or 3 heteroatoms selected    independently from N, O, and S, optionally substituted with 1, 2, or    3 substituents selected independently from R16;-   R15 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3    substituents selected independently from R21; a 5- or 6-membered    heterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S    and optionally substituted with 1, 2, or 3 substituents selected    from R21; or a 5- or 6-membered heteroaryl having 1, 2, or 3    heteroatoms selected from N, O, and S and optionally substituted    with 1, 2, or 3 substituents selected from R21;-   R16 is hydrogen; alkyl; aryl; heteroaryl containing 1 or 2    heteroatoms selected from N, O, and S; arylalkyl; heteroarylalkyl in    which the heteroaryl contains 1 or 2 heteroatoms selected from N, O,    and S;

amino; or

-   R17 is alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally    substituted with 1, 2, or 3 substituents independently selected from    R21; a 5- or 6-membered heterocycle, optionally substituted with 1,    2, or 3 substituents independently selected from R21; a 5- or    6-membered heteroaryl, optionally substituted with 1, 2, or 3    substituents independently selected from R21; or

wherein n is 0, 1, 2, or 3; and R18 is hydrogen or R17; or

-   R17 and R18, together with the nitrogen to which they are attached,    form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected    independently from N, O, and S, optionally substituted with 1, 2, or    3 substituents selected independently from R20;-   R19 is alkoxy; aryl, optionally substituted with 1, 2, or 3    substituents selected independently from R21; a 5- or 6-membered    heterocycle, optionally substituted with 1, 2, or 3 substituents    independently selected from R21; or a 5- or 6-membered heteroaryl,    optionally substituted with 1, 2, or 3 substituents independently    selected from R21;-   R20 is a 5- or 6-membered heterocycle having 1 or 2 heteroatoms    selected from N, O, and S and optionally substituted with 1, 2, or 3    substituents selected independently from R21; a 5- or 6-membered    heteroaryl, optionally substituted with 1, 2, or 3 substituents    selected independently from R21; or R21; and-   R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH₂,    —CON(CH₃)₂, alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl,-   with the exception of the compounds excluded from structural    formulae (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), and (A-7), below.

Non-limiting examples of

include the following, in which “X” is halogen, —CN, —CONH₂, —CON(CH₃)₂,C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxylalkyl, or C1-C4 alkoxylalkyl:

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-1):

wherein R3, R4, R5, and R6 are as defined in structural formula (A),PROVIDED THAT if R3 and R4 are both hydrogen and R5 is methyl, then R6cannot be ethyl or unsubstituted phenyl. In other embodiments, suchcompounds are specifically excluded from structural formula (A).

Structural Formula (A-1a).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which R5 is hydrogen; halogen;—CN; optionally substituted alkyl; or an optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing an N or O atom and optionally substitutedwith a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may contain 1 or2 heteroatoms selected from N, O, and S, and which is optionallysubstituted with a C1-C3 perfluoroalkyl. In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-1).

Structural Formula (A-1b).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1).

Structural Formula (A-1c).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1d).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which R4 is hydrogen, alkoxyl,or hydroxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1).

Structural Formula (A-1e).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen, alkoxyl, or hydroxyl, and    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1f).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen, alkoxyl, or hydroxyl and    -   b. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1g).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which R5 is hydrogen, alkyl,alkoxyl, alkylamino, CF₃, or, together with R6 and the carbon atoms towhich they are attached, forms a five-membered cycloalkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-1).

Structural Formula (A-1h).

Some embodiments specifically include and some embodiments only includecompounds include only compounds of structural formula (A-1) in which

-   -   a. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl and    -   b. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1i).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which R6 is independentlyhydrogen; alkenyl, alkyl, or phenyl, each optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1j).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen, alkoxyl, or hydroxyl,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl, and    -   c. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1k).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen, alkoxyl, or hydroxyl,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl, and    -   c. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1l).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen, alkoxyl, or hydroxyl,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl, and    -   c. R6 is a 5- or 6-membered heteroaryl that is substituted with        1, 2, or 3 substituents independently selected from the group        consisting of halogen, —CN, alkyl, perfluoroalkyl, alkoxy,        hydroxylalkyl, alkoxylalkyl, perfluoroalkoxyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1m).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen, alkoxyl, or hydroxyl,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl, and    -   c. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1n).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl, and    -   c. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1o).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is alkoxyl,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl, and    -   c. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1p).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydroxyl,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃, or, together        with R6 and the carbon atoms to which they are attached, forms a        five-membered cycloalkyl, and    -   c. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Structural Formula (A-1q).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-1) in which

-   -   a. R4 is hydrogen, alkoxyl, or hydroxyl,    -   b. R5 is hydrogen, alkyl, alkoxyl, alkylamino, or CF₃, and    -   c. R6 is hydrogen; alkenyl, alkyl, or phenyl, each optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —CN, alkyl,        perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,        perfluoroalkoxy,

a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl,alkoxylalkyl, perfluoroalkoxyl,

wherein n is 0, 1, or 2;

or R5 and R6, together with the carbon atoms to which they are attached,form a 5-membered cycloalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-1).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1a) and (2) compounds of any ofstructural formulae (A-1b), (A-1c), (A-1d), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1a) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1b), (A-1c), (A-1d), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1a) and (2) compounds of any ofstructural formulae (A-1b), (A-1c), (A-1d), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1a) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1b), (A-1c), (A-1d), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1b) and (2) compounds of any ofstructural formulae (A-1a), (A-1c), (A-1d), (A-1e), (A-1o), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1b) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1c), (A-1d), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1c) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1d), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1c) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1d), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1d) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1e), (A-1o), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1d) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1e), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1e) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1e) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1f), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1f) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1f) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1g),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1g) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1g) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1h) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1h) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1i) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1i) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1j) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1j) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1k) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1j), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1k) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1j), (A-1l), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1l) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1l) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1m), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1m) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1m) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1n), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1n) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1n) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1o), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1o) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1o) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1p),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1p) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1p) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o),and (A-1q). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1q) and (2) compounds of any ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1f),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o),and (A-1p). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-1q) and (2) compounds of up to 16(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) ofstructural formulae (A-1a), (A-1b), (A-1c), (A-1d), (A-1e), (A-1o),(A-1g), (A-1h), (A-1i), (A-1j), (A-1k), (A-1l), (A-1m), (A-1n), (A-1o),and (A-1p). In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-1). Each possiblecombination is specifically contemplated as if set forth explicitlyherein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-2):

wherein R3, R4, R5, R5′, R6, R7, R7′, R8, and R8′ are as defined instructural formula (A). In other embodiments, such compounds arespecifically excluded from structural formula (A).

Structural Formula (A-2a).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-2) in which R3, R4, R5, R5′, R7, R7′,R8, and R8′ are hydrogen. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-2).

Structural Formula (A-2b).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-2) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-2).

Structural Formula (A-2c).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-2) in which R7′ is hydrogen and R7 isa side chain selected from the group consisting of alkyl, perfluoroalkylalkoxyl, hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, eachoptionally substituted with 1-3 substituents selected from halogen, —CN,alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-2).

Structural Formula (A-2d).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-2) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-2).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2a) and (2) compounds of any ofstructural formulae (A-2b), (A-2c), and (A-2d). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-2). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2a) and (2) compounds of up to 3(e.g., 1, 2, or 3) of structural formulae (A-2b), (A-2c), and (A-2d). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-2). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2b) and (2) compounds of any ofstructural formulae (A-2a), (A-2c), and (A-2d). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-2). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2b) and (2) compounds of up to 3(e.g., 1, 2, or 3) of structural formulae (A-2a), (A-2c), and (A-2d). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-2). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2c) and (2) compounds of any ofstructural formulae (A-2a), (A-2b), and (A-2d). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-2). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2c) and (2) compounds of up to 3(e.g., 1, 2, or 3) of structural formulae (A-2a), (A-2b), and (A-2d). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-2). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2d) and (2) compounds of any ofstructural formulae (A-2a), (A-2b), and (A-2c). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-2). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-2d) and (2) compounds of up to 3(e.g., 1, 2, or 3) of structural formulae (A-2a), (A-2b), and (A-2c). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-2). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-3):

wherein:R3, R4, R6, and R7 are as defined in structural formula (A), PROVIDEDTHAT:

-   -   i. if R3 and R4 are hydrogen and R6 is optionally substituted        phenyl, then R7 cannot be optionally substituted phenyl,        hydrogen, methyl, or CH₂O(CH₂)₂;    -   ii. if R3 and R4 are hydrogen and R6 is methoxy, then R7 is not        methyl or unsubstituted phenyl;    -   iii. if R3 is ethyl, R4 is hydrogen, R7 is methyl, then R6 is        not fluorophenyl;    -   iv. if R3 is halogen and R4 and R7 are hydrogen, then R6 is not        bromophenyl; and    -   v. R6 and R7 cannot both be methyl if either:        -   i. R3 is halogen and R4 is hydrogen; or        -   ii. one of R3 and R4 is methyl and the other is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formula (A).

Structural Formula (A-3a).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, C1-C6 alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-3).

Structural Formula (A-3b).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R6 is alkenyl, oralkynyl, or phenyl, or a 5- or 6-membered heteroaryl, each optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of

of wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3c).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R7 is hydrogen; halogen;—CN; optionally substituted alkyl; or optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing an N or O atom and optionally substitutedwith a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may contain 1 or2 heteroatoms selected from N, O, and S, and which is optionallysubstituted with a C1-C3 perfluoroalkyl. In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3).

Structural Formula (A-3d).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R9 and R10 areindependently hydrogen, C2-C6 alkyl, alkoxylalkyl,perfluoroalkoxylalkyl, aryl, optionally substituted with 1, 2, or 3substituents independently selected from R21. In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3).

Structural Formula (A-3e).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R9 and R10 areindependently a 5- or 6-membered heterocycle, optionally substitutedwith 1, 2, or 3 substituents independently selected from R21. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3f).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R9 and R10 areindependently a 5- or 6-membered heteroaryl, optionally substituted with1, 2, or 3 substituents independently selected from R21; or

wherein n is 0, 1, 2, or 3 and R12 is as defined in structural formula(A). In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3g).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R9 and R10, together withthe nitrogen atom to which they are attached, form a heterocyclecontaining 1, 2, 3, or 4 heteroatoms selected from N, O and S,optionally substituted with 1, 2, or 3 substituents selectedindependently from R11, wherein R11 is defined as in structural formula(A). In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3h).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) which R6 is alkenyl, or alkynyl,or phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3i).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R7 is alkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3j).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R7 is methyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3k).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R7 is alkyl.    -   b. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3l).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A3) in which R3 is alkoxyl. Someembodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R3 is methoxy. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3m).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R7 is methyl and    -   b. R3 is alkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3n).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R7 is methyl;    -   b. R3 is alkoxyl; and    -   c. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3o).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R7 is methyl and    -   b. R3 is methoxy.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3p).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R7 is methyl;    -   b. R3 is methoxy; and    -   c. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3q).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R7 is alkyl and    -   b. R3 is alkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3r).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R7 is alkyl,    -   b. R3 is alkoxyl, and    -   c. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3s).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R6 is

wherein n is 0, 1, or 2, and R9 and R10 are defined as in structuralformula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3t).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3u).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3).

Structural Formula (A-3v).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3w).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R3 is methoxy and    -   b. R4 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3x).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R3 is methoxy,    -   b. R4 is hydrogen, and    -   c. R7 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3y).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R4 is methoxy and    -   b. R7 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3z).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R3 is hydrogen and    -   b. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3aa).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R4 is hydrogen and    -   b. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3bb).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3cc).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R3 is methoxy,    -   b. R4 is hydrogen, and    -   c. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3dd).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R3 is methoxy,    -   b. R4 is hydrogen,    -   c. R7 is methyl, and    -   d. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Structural Formula (A-3ee).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-3) in which

-   -   a. R4 is methoxy,    -   b. R7 is methyl, and    -   c. R6 is alkenyl, or alkynyl, or phenyl, or a 5- or 6-membered        heteroaryl, each optionally substituted with 1, 2, or 3        substituents independently selected from the group consisting of

wherein n is 0, 1, or 2;

in which R9 and R10 are defined as in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-3).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3a) and (2) compounds of any ofstructural formulae (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3a) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3b) and (2) compounds of any ofstructural formulae (A-3a), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3b) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3c) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3d), (A-3e), (A-3f), (A-3g),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3c) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3d) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3e), (A-3f), (A-3g),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3d) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3e), (A-3f), (A-3g), (A-3h), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3e) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3f), (A-3g),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3e) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3f), (A-3g), (A-3h), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3f) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3g),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-30 and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3g), (A-3h), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3g) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3g) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3h), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3h) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3h) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3i),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3i) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3i) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3j) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3j) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3k) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3k) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3l) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3l) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3m) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3m) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3n), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3n) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3n) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3o), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3o) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3o) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3p), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3p) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3p) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3q), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3q) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3q) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3r),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3r) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3r) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3s) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3s) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3t) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3t) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3u) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3u) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3v) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3v) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3w), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3w) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3w) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3x), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3x) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3x) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3y), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3y) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x),(A-3z), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3y) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3z), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3z) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x),(A-3y), (A-3aa), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3z) and (2) compounds of up to 30(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3aa),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3aa) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x),(A-3y), (A-3z), (A-3bb), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3aa) and (2) compounds of up to30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z),(A-3bb), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3bb) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x),(A-3y), (A-3z), (A-3aa), (A-3cc), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3bb) and (2) compounds of up to30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z),(A-3aa), (A-3cc), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3cc) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x),(A-3y), (A-3z), (A-3aa), (A-3bb), (A-3dd), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3cc) and (2) compounds of up to30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z),(A-3aa), (A-3bb), (A-3dd), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3dd) and (2) compounds of any ofstructural formulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f),(A-3g), (A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o),(A-3p), (A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x),(A-3y), (A-3z), (A-3aa), (A-3bb), (A-3cc), and (A-3ee). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-3). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3dd) and (2) compounds of up to30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z),(A-3aa), (A-3bb), (A-3cc), and (A-3ee). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3ee) and (2) compounds of any ofstructural (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g),(A-3h), (A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p),(A-3q), (A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y),(A-3z), (A-3aa), (A-3bb), (A-3cc), and (A-3dd). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-3). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-3ee) and (2) compounds of up to30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-3a), (A-3b), (A-3c), (A-3d), (A-3e), (A-3f), (A-3g), (A-3h),(A-3i), (A-3j), (A-3k), (A-3l), (A-3m), (A-3n), (A-3o), (A-3p), (A-3q),(A-3r), (A-3s), (A-3t), (A-3u), (A-3v), (A-3w), (A-3x), (A-3y), (A-3z),(A-3aa), (A-3bb), (A-3cc), and (A-3dd). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-3). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-4):

wherein R3, R4, R5, R5′, R6, R6′, R7, R8, and R8′ are as defined instructural formula (A). In other embodiments, such compounds arespecifically excluded from structural formula (A).

Structural Formula (A-4a).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-4) in which R3, R4, R5, R5′, R6, R6′,R8, and R8′ are hydrogen. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-4).

Structural Formula (A-4b).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-4) in which R7 is hydrogen; halogen;—CN; optionally substituted alkyl; or an optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing a nitrogen or oxygen atom and optionallysubstituted with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which maycontain 1 or 2 heteroatoms selected from N, O, and S, and which isoptionally substituted with a C1-C3 perfluoroalkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-4).

Structural Formula (A-4c).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-4) in which R7 is alkyl,perfluoroalkyl, alkoxyl, hydroxylalkyl, alkoxylalkyl, orperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-4).

Structural Formula (A-4d).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-4) in which R7 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-4).

Structural Formula (A-4e).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-4) in which R7 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-4).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4a) and (2) compounds of any ofstructural formulae (A-4b), (A-4c), (A-4d), and (A-4e). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-4). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4a) and (2) compounds of up to 4(e.g., 1, 2, 3, or 4) of structural formulae (A-4b), (A-4c), (A-4d), and(A-4e). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-4). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4b) and (2) compounds of any ofstructural formulae (A-4a), (A-4c), (A-4d), and (A-4e). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-4). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4b) and (2) compounds of up to 4(e.g., 1, 2, 3, or 4) of structural formulae (A-4a), (A-4c), (A-4d), and(A-4e). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-4). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4c) and (2) compounds of any ofstructural formulae (A-4a), (A-4b), (A-4d), and (A-4e). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-4). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4c) and (2) compounds of up to 4(e.g., 1, 2, 3, or 4) of structural formulae (A-4a), (A-4b), (A-4d), and(A-4e). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-4). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4d) and (2) compounds of any ofstructural formulae (A-4a), (A-4b), (A-4c), and (A-4e). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-4). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4d) and (2) compounds of up to 4(e.g., 1, 2, 3, or 4) of structural formulae (A-4a), (A-4b), (A-4c), and(A-4e). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-4). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4e) and (2) compounds of any ofstructural formulae (A-4a), (A-4b), (A-4c), and (A-4d). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-4). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-4e) and (2) compounds of up to 4(e.g., 1, 2, 3, or 4) of structural formulae (A-4a), (A-4b), (A-4c), and(A-4d). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-4). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-5):

wherein R3, R4, R6, R7, and R8 are as defined in structural formula (A).In other embodiments, such compounds are specifically excluded fromstructural formula (A).

Structural Formula (A-5a).

Some embodiments include only those compounds of structural formula(A-5) in which R3 and R4 are hydrogen. In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-5).

Structural Formula (A-5b).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-5) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-5).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-5a) and (2) compounds ofstructural formula (A-5b). In other embodiments, (1) compounds ofstructural formula (A-5a) and (2) compounds of structural formula (A-5b)compounds are specifically excluded from structural formulae (A) and/or(A-5).

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-6a):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-6a1).

Some embodiments include only those compounds of structural formula(A-6a) in which R3 is hydrogen. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-6a).

Structural Formula (A-6a2).

Some embodiments include only those compounds of structural formula(A-6a) in which R4 is hydrogen. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-6a).

Structural Formula (A-6a3).

Some embodiments include only those compounds of structural formula(A-6a) in which R3 and R4 are hydrogen. In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-6a).

Structural Formula (A-6a4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6a) in which R6 is hydrogen; halogen;—CN; optionally substituted alkyl; or optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing a nitrogen or oxygen atom and optionallysubstituted with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which maycontain 1 or 2 heteroatoms selected from N, O, and S, and which isoptionally substituted with a C1-C3 perfluoroalkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a).

Structural Formula (A-6a5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6a) in which R6 is C1-C6 alkyl, C1-C6perfluoroalkyl, C1-C6 alkoxyl, C1-C6 hydroxylalkyl, C1-C6 alkoxylalkyl,or C1-C6 perfluoroalkoxyl. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-6a).

Structural Formula (A-6a6).

Some embodiments include only those compounds of structural formula(A-6a) in which

-   -   a. R3 is hydrogen and    -   b. R6 is hydrogen; halogen; —CN; optionally substituted alkyl;        or optionally substituted alkoxyl. Optional substituents for the        alkyl and for the alkoxyl are (1) a C1-C6 hydrocarbon chain        containing a nitrogen or oxygen atom and optionally substituted        with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may        contain 1 or 2 heteroatoms selected from N, O, and S, and which        is optionally substituted with a C1-C3 perfluoroalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a).

Structural Formula (A-6a7).

Some embodiments include only those compounds of structural formula(A-6a) in which

-   -   a. R4 is hydrogen and    -   b. R6 is hydrogen; halogen; —CN; optionally substituted alkyl;        or optionally substituted alkoxyl. Optional substituents for the        alkyl and for the alkoxyl are (1) a C1-C6 hydrocarbon chain        containing a nitrogen or oxygen atom and optionally substituted        with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may        contain 1 or 2 heteroatoms selected from N, O, and S, and which        is optionally substituted with a C1-C3 perfluoroalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a).

Structural Formula (A-6a8).

Some embodiments include only those compounds of structural formula(A-6a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen; halogen; —CN; optionally substituted alkyl;        or optionally substituted alkoxyl. Optional substituents for the        alkyl and for the alkoxyl are (1) a C1-C6 hydrocarbon chain        containing a nitrogen or oxygen atom and optionally substituted        with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may        contain 1 or 2 heteroatoms selected from N, O, and S, and which        is optionally substituted with a C1-C3 perfluoroalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a).

Structural Formula (A-6a9).

Some embodiments include only those compounds of structural formula(A-6a) in which

-   -   a. R3 is hydrogen and    -   b. R6 is C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl, C1-C6        hydroxylalkyl, C1-C6 alkoxylalkyl, or C1-C6 perfluoroalkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a).

Structural Formula (A-6a10).

Some embodiments include only those compounds of structural formula(A-6a) in which

-   -   a. R4 is hydrogen and    -   b. R6 is C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl, C1-C6        hydroxylalkyl, C1-C6 alkoxylalkyl, or C1-C6 perfluoroalkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a).

Structural Formula (A-6a11).

Some embodiments include only those compounds of structural formula(A-6a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl, C1-C6        hydroxylalkyl, C1-C6 alkoxylalkyl, or C1-C6 perfluoroalkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a).

Structural Formula (A-6a12).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6a) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-6a).

Structural Formula (A-6a13).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6a) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a1) and (2) compounds of any ofstructural formulae (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6),(A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a1) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7), (A-6a8),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a2) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a3), (A-6a4), (A-6a5), (A-6a6),(A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a2) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7), (A-6a8),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a3) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a4), (A-6a5), (A-6a6),(A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a3) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a4), (A-6a5), (A-6a6), (A-6a7), (A-6a8),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a4) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a5), (A-6a6),(A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a4) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a5), (A-6a6), (A-6a7), (A-6a8),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a5) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a6),(A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a5) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a6), (A-6a7), (A-6a8),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a6) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a6) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a7), (A-6a8),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a7) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a6), (A-6a8), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a7) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a8),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a8) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a6), (A-6a7), (A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a8) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7),(A-6a9), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a9) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a6), (A-6a7), (A-6a8), (A-6a10), (A-6a11), (A-6a12), and (A-6a13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a9) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7),(A-6a8), (A-6a10), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a10) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a6), (A-6a7), (A-6a8), (A-6a9), (A-6a11), (A-6a12), and (A-6a13). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a10) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7),(A-6a8), (A-6a9), (A-6a11), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a11) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a6), (A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a12), and (A-6a13). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a11) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7),(A-6a8), (A-6a9), (A-6a10), (A-6a12), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a12) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a6), (A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), and (A-6a13). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a12) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7),(A-6a8), (A-6a9), (A-6a10), (A-6a11), and (A-6a13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a13) and (2) compounds of any ofstructural formulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5),(A-6a6), (A-6a7), (A-6a8), (A-6a9), (A-6a10), (A-6a11), and (A-6a12). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6a13) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6a1), (A-6a2), (A-6a3), (A-6a4), (A-6a5), (A-6a6), (A-6a7),(A-6a8), (A-6a9), (A-6a10), (A-6a11), and (A-6a12). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-6b):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-6b1).

Some embodiments include only those compounds of structural formula(A-6b) in which R3 is hydrogen. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-6b).

Structural Formula (A-6b2).

Some embodiments include only those compounds of structural formula(A-6b) in which R4 is hydrogen. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-6b).

Structural Formula (A-6b3).

Some embodiments include only those compounds of structural formula(A-6b) in which R3 and R4 are hydrogen. In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-6b).

Structural Formula (A-6b4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6b) in which R6 is hydrogen; halogen;—CN; optionally substituted alkyl; or optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing a nitrogen or oxygen atom and optionallysubstituted with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which maycontain 1 or 2 heteroatoms selected from N, O, and S, and which isoptionally substituted with a C1-C3 perfluoroalkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b).

Structural Formula (A-6b5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6b) in which R6 is C1-C6 alkyl, C1-C6perfluoroalkyl, C1-C6 alkoxyl, C1-C6 hydroxylalkyl, C1-C6 alkoxylalkyl,or C1-C6 perfluoroalkoxyl. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-6b).

Structural Formula (A-6b6).

Some embodiments include only those compounds of structural formula(A-6b) in which

-   -   a. R3 is hydrogen and    -   b. R6 is hydrogen; halogen; —CN; optionally substituted alkyl;        or optionally substituted alkoxyl. Optional substituents for the        alkyl and for the alkoxyl are (1) a C1-C6 hydrocarbon chain        containing a nitrogen or oxygen atom and optionally substituted        with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may        contain 1 or 2 heteroatoms selected from N, O, and S, and which        is optionally substituted with a C1-C3 perfluoroalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b).

Structural Formula (A-6b7).

Some embodiments include only those compounds of structural formula(A-6b) in which

-   -   a. R4 is hydrogen and    -   b. R6 is hydrogen; halogen; —CN; optionally substituted alkyl;        or optionally substituted alkoxyl. Optional substituents for the        alkyl and for the alkoxyl are (1) a C1-C6 hydrocarbon chain        containing a nitrogen or oxygen atom and optionally substituted        with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may        contain 1 or 2 heteroatoms selected from N, O, and S, and which        is optionally substituted with a C1-C3 perfluoroalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b).

Structural Formula (A-6b8).

Some embodiments include only those compounds of structural formula(A-6b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen; halogen; —CN; optionally substituted alkyl;        or optionally substituted alkoxyl. Optional substituents for the        alkyl and for the alkoxyl are (1) a C1-C6 hydrocarbon chain        containing a nitrogen or oxygen atom and optionally substituted        with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which may        contain 1 or 2 heteroatoms selected from N, O, and S, and which        is optionally substituted with a C1-C3 perfluoroalkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b).

Structural Formula (A-6b9).

Some embodiments include only those compounds of structural formula(A-6b) in which

-   -   a. R3 is hydrogen and    -   b. R6 is C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl, C1-C6        hydroxylalkyl, C1-C6 alkoxylalkyl, or C1-C6 perfluoroalkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b).

Structural Formula (A-6b10).

Some embodiments include only those compounds of structural formula(A-6b) in which

-   -   a. R4 is hydrogen and    -   b. R6 is C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl, C1-C6        hydroxylalkyl, C1-C6 alkoxylalkyl, or C1-C6 perfluoroalkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b).

Structural Formula (A-6b11).

Some embodiments include only those compounds of structural formula(A-6b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl, C1-C6        hydroxylalkyl, C1-C6 alkoxylalkyl, or C1-C6 perfluoroalkoxyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b).

Structural Formula (A-6b12).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6b) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-6b).

Structural Formula (A-6b13).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-6b) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b1) and (2) compounds of any ofstructural formulae (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6),(A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b1) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7), (A-6b8),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b2) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b3), (A-6b4), (A-6b5), (A-6b6),(A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b2) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7), (A-6b8),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b3) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b4), (A-6b5), (A-6b6),(A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b3) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b4), (A-6b5), (A-6b6), (A-6b7), (A-6b8),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b4) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b5), (A-6b6),(A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b4) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b5), (A-6b6), (A-6b7), (A-6b8),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b5) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b6),(A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b5) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b6), (A-6b7), (A-6b8),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b6) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b6) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b7), (A-6b8),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b7) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b8), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b7) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b8),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b8) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b7), (A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b8) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7),(A-6b9), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b9) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b7), (A-6b8), (A-6b10), (A-6b11), (A-6b12), and (A-6b13).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b9) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7),(A-6b8), (A-6b10), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b10) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b7), (A-6b8), (A-6b9), (A-6b11), (A-6b12), and (A-6b13). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b10) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7),(A-6b8), (A-6b9), (A-6b11), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b11) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b12), and (A-6b13). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b11) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7),(A-6b8), (A-6b9), (A-6b10), (A-6b12), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b12) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), and (A-6b13). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b12) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7),(A-6b8), (A-6b9), (A-6b10), (A-6b11), and (A-6b13). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b13) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), and (A-6b12). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b13) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7),(A-6b8), (A-6b9), (A-6b10), (A-6b11), and (A-6b12). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-6b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b13) and (2) compounds of any ofstructural formulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5),(A-6b6), (A-6b7), (A-6b8), (A-6b9), (A-6b10), (A-6b11), or (A-6b12). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-6b). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-6b13) and (2) compounds of up to12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of structuralformulae (A-6b1), (A-6b2), (A-6b3), (A-6b4), (A-6b5), (A-6b6), (A-6b7),(A-6b8), (A-6b9), (A-6b10), (A-6b11), or (A-6b12). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-6b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-7a), which can exist as amixture of two tautomers:

wherein R3, R4, and R6 are as defined in structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formula (A).

Structural Formula (A-7a1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7a) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7a).

Structural Formula (A-7a2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7a) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7a).

Structural Formula (A-7a3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7a) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7a).

Structural Formula (A-7a4).

Some embodiments include only those compounds of formula (A-7a) in whichR3 and R4 are hydrogen. In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-7a).

Structural Formula (A-7a5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7a) in which R6 is hydrogen; halogen;—CN; optionally substituted alkyl; or optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing a nitrogen or oxygen atom and optionallysubstituted with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which maycontain 1 or 2 heteroatoms selected from N, O, and S, and which isoptionally substituted with a C1-C3 perfluoroalkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7a).

Structural Formula (A-7a6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7a) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-7a).

Structural Formula (A-7a7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7a) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a1) and (2) compounds of any ofstructural formulae (A-7a2), (A-7a3), (A-7a4), (A-7a5), (A-7a6), and(A-7a7). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-7a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a1) and (2) compounds of up to 6(e.g., 1, 2, 3, 4, 5, or 6) of structural formulae (A-7a2), (A-7a3),(A-7a4), (A-7a5), (A-7a6), and (A-7a7). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-7a). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a2) and (2) compounds of any ofstructural formulae (A-7a1), (A-7a3), (A-7a4), (A-7a5), (A-7a6), and(A-7a7). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-7a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a2) and (2) compounds of up to 6(e.g., 1, 2, 3, 4, 5, or 6) of structural formulae (A-7a1), (A-7a3),(A-7a4), (A-7a5), (A-7a6), and (A-7a7). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-7a). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a3) and (2) compounds of any ofstructural formulae (A-7a1), (A-7a2), (A-7a4), (A-7a5), (A-7a6), and(A-7a7). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-7a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a3) and (2) compounds of up to 6(e.g., 1, 2, 3, 4, 5, or 6) of structural formulae (A-7a1), (A-7a2),(A-7a4), (A-7a5), (A-7a6), and (A-7a7). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-7a). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a4) and (2) compounds of any ofstructural formulae (A-7a1), (A-7a2), (A-7a3), (A-7a5), (A-7a6), and(A-7a7). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-7a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a4) and (2) compounds of up to 6(e.g., 1, 2, 3, 4, 5, or 6) of structural formulae (A-7a1), (A-7a2),(A-7a3), (A-7a5), (A-7a6), and (A-7a7). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-7a). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a5) and (2) compounds of any ofstructural formulae (A-7a1), (A-7a2), (A-7a3), (A-7a4), (A-7a6), and(A-7a7). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-7a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a5) and (2) compounds of up to 6(e.g., 1, 2, 3, 4, 5, or 6) of structural formulae (A-7a1), (A-7a2),(A-7a3), (A-7a4), (A-7a6), and (A-7a7). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-7a). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a6) and (2) compounds of any ofstructural formulae (A-7a1), (A-7a2), (A-7a3), (A-7a4), (A-7a5), and(A-7a7). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-7a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a6) and (2) compounds of up to 6(e.g., 1, 2, 3, 4, 5, or 6) of structural formulae (A-7a1), (A-7a2),(A-7a3), (A-7a4), (A-7a5), and (A-7a7). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-7a). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a7) and (2) compounds of any ofstructural formulae (A-7a1), (A-7a2), (A-7a3), (A-7a4), (A-7a5), and(A-7a6). In other embodiments, such compounds are specifically excludedfrom structural formulae (A) and/or (A-7a). Each possible combination isspecifically contemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7a7) and (2) compounds of up to 6(e.g., 1, 2, 3, 4, 5, or 6) of structural formulae (A-7a1), (A-7a2),(A-7a3), (A-7a4), (A-7a5), and (A-7a6). In other embodiments, suchcompounds are specifically excluded from structural formulae (A) and/or(A-7a). Each possible combination is specifically contemplated as if setforth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-7b):

wherein R3, R4, and R6 are as defined in structural formula (A) and R7is hydrogen or C1-C3 alkyl. In other embodiments, such compounds arespecifically excluded from structural formula (A).

Structural Formula (A-7b1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b).

Structural Formula (A-7b2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b).

Structural Formula (A-7b3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R7 is C1-C3 alkyl. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R7 is methyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b).

Structural Formula (A-7b6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R6 is hydrogen; halogen;—CN; optionally substituted alkyl; or optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing a nitrogen or oxygen atom and optionallysubstituted with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which maycontain 1 or 2 heteroatoms selected from N, O, and S, and which isoptionally substituted with a C1-C3 perfluoroalkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b).

Structural Formula (A-7b7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-7b).

Structural Formula (A-7b8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R3 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R3 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R7 is C1-C3 alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b12).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R3 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R7 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b13).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R4 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b14).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R4 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R7 is C1-C3 alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b15).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R4 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R7 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b16).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R3 and R4 are hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b17).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R3 and R4 are hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R7 is C1-C3 alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Structural Formula (A-7b18).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7b) in which

-   -   a. R3 and R4 are hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R7 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b1) and (2) compounds of any ofstructural formulae (A-7b2), (A-7b3), (A-7b4), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b1) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b2), (A-7b3), (A-7b4), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b2) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b3), (A-7b4), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b2) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b3), (A-7b4), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b3) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b4), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b3) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b4), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b4) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b4) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b5), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b5) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b5) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b6),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b6) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b6) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b7) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b7) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b8) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b8) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b9), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b9) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b9) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b10), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b10) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b10) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b11), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b11) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b11) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b12), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b12) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b12) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b13),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b13) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b13) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b14), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b14) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b14) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b15), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b15) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b15) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b16), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b16) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b15), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b16) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b15), (A-7b17), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b17) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b15), (A-7b16), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b17) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b15), (A-7a16), and (A-7b18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b18) and (2) compounds of any ofstructural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b15), (A-7b16), and (A-7b17). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7b18) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7b1), (A-7b2), (A-7b3), (A-7b4), (A-7b5),(A-7b6), (A-7b7), (A-7b8), (A-7b9), (A-7b10), (A-7b11), (A-7b12),(A-7b13), (A-7b14), (A-7b15), (A-7b16), and (A-7b17). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-7c):

wherein R3, R4, and R6 are as defined in structural formula (A) and R5is hydrogen or C1-C3 alkyl. In other embodiments, such compounds arespecifically excluded from structural formula (A).

Structural Formula (A-7c1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c).

Structural Formula (A-7c2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c).

Structural Formula (A-7c3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R5 is C1-C3 alkyl. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R5 is methyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c).

Structural Formula (A-7c6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R6 is hydrogen; halogen;—CN; optionally substituted alkyl; or optionally substituted alkoxyl.Optional substituents for the alkyl and for the alkoxyl are (1) a C1-C6hydrocarbon chain containing a nitrogen or oxygen atom and optionallysubstituted with a C1-C3 perfluoroalkyl, and (2) a cycloalkyl which maycontain 1 or 2 heteroatoms selected from N, O, and S, and which isoptionally substituted with a C1-C3 perfluoroalkyl. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c).

Structural Formula (A-7c7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R6 is a side chainselected from the group consisting of alkyl, perfluoroalkyl, alkoxyl,hydroxylalkyl, alkoxylalkyl, and perfluoroalkoxyl, each optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, andperfluoroalkoxyl. In other embodiments, such compounds are specificallyexcluded from structural formulae (A) and/or (A-7c).

Structural Formula (A-7c8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R6 is alkenyl, alkyne,phenyl, or a 5- or 6-membered heteroaryl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of

wherein n is 0, 1, or 2;

andR9 and R10 are as defined in connection with structural formula (A). Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R3 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R3 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R5 is C1-C3 alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c12).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R3 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R5 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c13).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R4 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c14).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R4 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R5 is C1-C3 alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c15).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R4 is hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R5 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c16).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R3 and R4 are hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c17).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R3 and R4 are hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R5 is C1-C3 alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Structural Formula (A-7c18).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-7c) in which

-   -   a. R3 and R4 are hydrogen; and    -   b. R6 is

wherein n is 0, 1, or 2; or,

and R9 and R10 are as defined in connection with structural formula (A);and

-   -   c. R5 is methyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-7c).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c1) and (2) compounds of any ofstructural formulae (A-7c2), (A-7c3), (A-7c4), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c1) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c2), (A-7c3), (A-7c4), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c2) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c3), (A-7c4), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c2) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c3), (A-7c4), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c3) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c4), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c3) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c4), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c4) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c4) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c5), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c5) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c5) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c6),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c6) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c6) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c7) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c7) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c8) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c8) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c9), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c9) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c9) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c10), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c10) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c10) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c11), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c11) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c11) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c12), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c12) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c12) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c13),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c13) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c13) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c14), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c14) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c14) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c15), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c15) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c15) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c16), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c16) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c15), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c16) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c15), (A-7c17), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c17) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c15), (A-7c16), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c17) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c15), (A-7a16), and (A-7c18). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c18) and (2) compounds of any ofstructural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c15), (A-7c16), and (A-7c17). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-7c18) and (2) compounds of up to17 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17)of structural formulae (A-7c1), (A-7c2), (A-7c3), (A-7c4), (A-7c5),(A-7c6), (A-7c7), (A-7c8), (A-7c9), (A-7c10), (A-7c11), (A-7c12),(A-7c13), (A-7c14), (A-7c15), (A-7c16), and (A-7c17). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-7c). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-8a):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-8a1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-8a).

Structural Formula (A-8a2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-8a).

Structural Formula (A-8a3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Structural Formula (A-8a11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

-   -   c. R9 is alkyl or alkoxylalkyl, and    -   d. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a1) and (2) compounds of any ofstructural formulae (A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a6),(A-8a7), (A-8a8), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a6), (A-8a7), (A-8a8), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a2) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a3), (A-8a4), (A-8a5), (A-8a6),(A-8a7), (A-8a8), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a3), (A-8a4), (A-8a5), (A-8a6), (A-8a7), (A-8a8), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a3) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a4), (A-8a5), (A-8a6),(A-8a7), (A-8a8), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a4), (A-8a5), (A-8a6), (A-8a7), (A-8a8), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a4) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a5), (A-8a6),(A-8a7), (A-8a8), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a5), (A-8a6), (A-8a7), (A-8a8), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a5) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a6),(A-8a7), (A-8a8), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a6), (A-8a7), (A-8a8), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a6) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5),(A-8a7), (A-8a8), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a7), (A-8a8), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a7) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5),(A-8a6), (A-8a8), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a7) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a6), (A-8a8), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a8) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5),(A-8a6), (A-8a7), (A-8a9), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a8) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a6), (A-8a7), (A-8a9),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a9) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5),(A-8a6), (A-8a7), (A-8a8), (A-8a10), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a6), (A-8a7), (A-8a8),(A-8a10), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a10) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5),(A-8a6), (A-8a7), (A-8a8), (A-8a9), and (A-8a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a6), (A-8a7), (A-8a8),(A-8a9), and (A-8a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a11) and (2) compounds of any ofstructural formulae (A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5),(A-8a6), (A-8a7), (A-8a8), (A-8a9), and (A-8a10). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8a11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8a1), (A-8a2), (A-8a3), (A-8a4), (A-8a5), (A-8a6), (A-8a7), (A-8a8),(A-8a9), and (A-8a10). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-8b):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-8b1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-8b).

Structural Formula (A-8b2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-8b).

Structural Formula (A-8b3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Structural Formula (A-8b11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-8b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

-   -   c. R9 is alkyl or alkoxylalkyl, and    -   d. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-8b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b1) and (2) compounds of any ofstructural formulae (A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b6),(A-8b7), (A-8b8), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b6), (A-8b7), (A-8b8), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b2) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b3), (A-8b4), (A-8b5), (A-8b6),(A-8b7), (A-8b8), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b3), (A-8b4), (A-8b5), (A-8b6), (A-8b7), (A-8b8), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b3) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b4), (A-8b5), (A-8b6),(A-8b7), (A-8b8), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b4), (A-8b5), (A-8b6), (A-8b7), (A-8b8), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b4) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b5), (A-8b6),(A-8b7), (A-8b8), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b5), (A-8b6), (A-8b7), (A-8b8), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b5) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b6),(A-8b7), (A-8b8), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b6), (A-8b7), (A-8b8), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b6) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5),(A-8b7), (A-8b8), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b7), (A-8b8), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b7) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5),(A-8b6), (A-8b8), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b7) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b6), (A-8b8), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b8) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5),(A-8b6), (A-8b7), (A-8b9), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b8) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b6), (A-8b7), (A-8b9),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b9) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5),(A-8b6), (A-8b7), (A-8b8), (A-8b10), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b6), (A-8b7), (A-8b8),(A-8b10), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b10) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5),(A-8b6), (A-8b7), (A-8b8), (A-8b9), and (A-8b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b6), (A-8b7), (A-8b8),(A-8b9), and (A-8b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b11) and (2) compounds of any ofstructural formulae (A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5),(A-8b6), (A-8b7), (A-8b8), (A-8b9), and (A-8b10). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-8b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-8b11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-8b1), (A-8b2), (A-8b3), (A-8b4), (A-8b5), (A-8b6), (A-8b7), (A-8b8),(A-8b9), and (A-8b10). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-8b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-9a):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-9a1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-9a).

Structural Formula (A-9a2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-9a).

Structural Formula (A-9a3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Structural Formula (A-9a11).

Some embodiments include only those compounds of structural formula(A-9a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

-   -   c. R9 is alkyl or alkoxylalkyl, and    -   d. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a1) and (2) compounds of any ofstructural formulae (A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a6),(A-9a7), (A-9a8), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a6), (A-9a7), (A-9a8), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a2) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a3), (A-9a4), (A-9a5), (A-9a6),(A-9a7), (A-9a8), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a3), (A-9a4), (A-9a5), (A-9a6), (A-9a7), (A-9a8), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a3) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a4), (A-9a5), (A-9a6),(A-9a7), (A-9a8), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a4), (A-9a5), (A-9a6), (A-9a7), (A-9a8), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a4) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a5), (A-9a6),(A-9a7), (A-9a8), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a5), (A-9a6), (A-9a7), (A-9a8), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a5) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a6),(A-9a7), (A-9a8), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a6), (A-9a7), (A-9a8), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a6) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5),(A-9a7), (A-9a8), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a7), (A-9a8), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a7) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5),(A-9a6), (A-9a8), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a7) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a6), (A-9a8), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a8) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5),(A-9a6), (A-9a7), (A-9a9), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a8) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a6), (A-9a7), (A-9a9),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a9) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5),(A-9a6), (A-9a7), (A-9a8), (A-9a10), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a6), (A-9a7), (A-9a8),(A-9a10), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a10) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5),(A-9a6), (A-9a7), (A-9a8), (A-9a9), and (A-9a11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a6), (A-9a7), (A-9a8),(A-9a9), and (A-9a11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a11) and (2) compounds of any ofstructural formulae (A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5),(A-9a6), (A-9a7), (A-9a8), (A-9a9), and (A-9a10). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9a). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9a11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9a1), (A-9a2), (A-9a3), (A-9a4), (A-9a5), (A-9a6), (A-9a7), (A-9a8),(A-9a9), and (A-9a10). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9a). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-9b):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-9b1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which R3 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-9b).

Structural Formula (A-9b2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which R4 is hydrogen. In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-9b).

Structural Formula (A-9b3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-9b4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-9b5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-9b6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-967).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-968).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-9b9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-9b10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Structural Formula (A-9b11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-9b) in which

-   -   a. R3 and R4 are hydrogen and R6 is

-   -   b. R9 is alkyl or alkoxylalkyl, and    -   c. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-9b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b1) and (2) compounds of any ofstructural formulae (A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-9b6),(A-967), (A-968), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-9b6), (A-967), (A-968), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b2) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b3), (A-9b4), (A-9b5), (A-9b6),(A-967), (A-968), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b3), (A-9b4), (A-9b5), (A-9b6), (A-967), (A-968), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b3) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b4), (A-9b5), (A-9b6),(A-967), (A-968), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b4), (A-9b5), (A-9b6), (A-967), (A-968), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b4) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b5), (A-9b6),(A-967), (A-968), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b5), (A-9b6), (A-967), (A-968), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b5) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b6),(A-967), (A-968), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b6), (A-967), (A-968), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b6) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5),(A-967), (A-968), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-967), (A-968), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-967) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5),(A-9b6), (A-968), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-967) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-9b6), (A-968), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-968) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5),(A-9b6), (A-967), (A-9b9), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-968) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-9b6), (A-967), (A-9b9),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b9) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5),(A-9b6), (A-967), (A-968), (A-9b10), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-9b6), (A-967), (A-968),(A-9b10), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b10) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5),(A-9b6), (A-967), (A-968), (A-9b9), and (A-9b11). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-9b6), (A-967), (A-968),(A-9b9), and (A-9b11). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b11) and (2) compounds of any ofstructural formulae (A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5),(A-9b6), (A-967), (A-968), (A-9b9), and (A-9b10). In other embodiments,such compounds are specifically excluded from structural formulae (A)and/or (A-9b). Each possible combination is specifically contemplated asif set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-9b11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-9b1), (A-9b2), (A-9b3), (A-9b4), (A-9b5), (A-9b6), (A-967), (A-968),(A-9b9), and (A-9b10). In other embodiments, such compounds arespecifically excluded from structural formulae (A) and/or (A-9b). Eachpossible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-10a):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-10a1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which R3 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which R4 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Structural Formula (A-10a11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

-   -   c. R9 is alkyl or alkoxylalkyl, and    -   d. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a1) and (2) compounds of any ofstructural formulae (A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a6),(A-10a7), (A-10a8), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a6), (A-10a7), (A-10a8),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a2) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a3), (A-10a4), (A-10a5), (A-10a6),(A-10a7), (A-10a8), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a3), (A-10a4), (A-10a5), (A-10a6), (A-10a7), (A-10a8),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a3) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a2), (A-10a4), (A-10a5), (A-10a6),(A-10a7), (A-10a8), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a4), (A-10a5), (A-10a6), (A-10a7), (A-10a8),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a4) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a5), (A-10a6),(A-10a7), (A-10a8), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a5), (A-10a6), (A-10a7), (A-10a8),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a5) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a6),(A-10a7), (A-10a8), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a6), (A-10a7), (A-10a8),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a6) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5),(A-10a7), (A-10a8), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a7), (A-10a8),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a7) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5),(A-10a6), (A-10a8), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a7) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a6), (A-10a8),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a8) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5),(A-10a6), (A-10a7), (A-10a9), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a8) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a6), (A-10a7),(A-10a9), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a9) and (2) compounds of any ofstructural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5),(A-10a6), (A-10a7), (A-10a8), (A-10a10), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a6), (A-10a7),(A-10a8), (A-10a10), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a10) and (2) compounds of anyof structural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5),(A-10a6), (A-10a7), (A-10a8), (A-10a9), and (A-10a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a6), (A-10a7),(A-10a8), (A-10a9), and (A-10a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a11) and (2) compounds of anyof structural formulae (A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5),(A-10a6), (A-10a7), (A-10a8), (A-10a9), and (A-10a10). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10a11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10a1), (A-10a2), (A-10a3), (A-10a4), (A-10a5), (A-10a6), (A-10a7),(A-10a8), (A-10a9), and (A-10a10). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-10b):

wherein:R3, R4, and R6 are as defined in structural formula (A). In otherembodiments, such compounds are specifically excluded from structuralformula (A).

Structural Formula (A-10b1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which R3 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which R4 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Structural Formula (A-10b11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-10b) in which

-   -   a. R3 and R4 are hydrogen and R6 is

-   -   b. R9 is alkyl or alkoxylalkyl, and    -   c. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-10b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b1) and (2) compounds of any ofstructural formulae (A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b6),(A-10b7), (A-10b8), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b6), (A-10b7), (A-10b8),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b2) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b3), (A-10b4), (A-10b5), (A-10b6),(A-10b7), (A-10b8), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b3), (A-10b4), (A-10b5), (A-10b6), (A-10b7), (A-10b8),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b3) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b2), (A-10b4), (A-10b5), (A-10b6),(A-10b7), (A-10b8), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b4), (A-10b5), (A-10b6), (A-10b7), (A-10b8),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b4) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b5), (A-10b6),(A-10b7), (A-10b8), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b5), (A-10b6), (A-10b7), (A-10b8),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b5) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b6),(A-10b7), (A-10b8), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b6), (A-10b7), (A-10b8),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b6) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5),(A-10b7), (A-10b8), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b7), (A-10b8),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b7) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5),(A-10b6), (A-10b8), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b7) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b6), (A-10b8),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b8) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5),(A-10b6), (A-10b7), (A-10b9), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b8) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b6), (A-10b7),(A-10b9), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b9) and (2) compounds of any ofstructural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5),(A-10b6), (A-10b7), (A-10b8), (A-10b10), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b6), (A-10b7),(A-10b8), (A-10b10), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b10) and (2) compounds of anyof structural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5),(A-10b6), (A-10b7), (A-10b8), (A-10b9), and (A-10b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b6), (A-10b7),(A-10b8), (A-10b9), and (A-10b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b11) and (2) compounds of anyof structural formulae (A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5),(A-10b6), (A-10b7), (A-10b8), (A-10b9), and (A-10b10). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-10b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-10b11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-10b1), (A-10b2), (A-10b3), (A-10b4), (A-10b5), (A-10b6), (A-10b7),(A-10b8), (A-10b9), and (A-10b10). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-10b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-11a):

wherein:R3, R4, and R6 are as defined in structural formula (A); and R5 ishydrogen or C1-C3 alkyl. In other embodiments, such compounds arespecifically excluded from structural formula (A).

Structural Formula (A-11a1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which R3 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which R4 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Structural Formula (A-11a11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11a) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

-   -   c. R9 is alkyl or alkoxylalkyl, and    -   d. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a1) and (2) compounds of any ofstructural formulae (A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a6),(A-11a7), (A-11a8), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a6), (A-11a7), (A-11a8),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a2) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a3), (A-11a4), (A-11a5), (A-11a6),(A-11a7), (A-11a8), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a3), (A-11a4), (A-11a5), (A-11a6), (A-11a7), (A-11a8),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a3) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a2), (A-11a4), (A-11a5), (A-11a6),(A-11a7), (A-11a8), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a4), (A-11a5), (A-11a6), (A-11a7), (A-11a8),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a4) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a5), (A-11a6),(A-11a7), (A-11a8), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a5), (A-11a6), (A-11a7), (A-11a8),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a5) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a6),(A-11a7), (A-11a8), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a6), (A-11a7), (A-11a8),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a6) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5),(A-11a7), (A-11a8), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a7), (A-11a8),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a7) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5),(A-11a6), (A-11a8), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a7) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a6), (A-11a8),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a8) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5),(A-11a6), (A-11a7), (A-11a9), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a8) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a6), (A-11a7),(A-11a9), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a9) and (2) compounds of any ofstructural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5),(A-11a6), (A-11a7), (A-11a8), (A-11a10), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a6), (A-11a7),(A-11a8), (A-11a10), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a10) and (2) compounds of anyof structural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5),(A-11a6), (A-11a7), (A-11a8), (A-11a9), and (A-11a11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a6), (A-11a7),(A-11a8), (A-11a9), and (A-11a11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a11) and (2) compounds of anyof structural formulae (A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5),(A-11a6), (A-11a7), (A-11a8), (A-11a9), and (A-11a10). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11a). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11a11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11a1), (A-11a2), (A-11a3), (A-11a4), (A-11a5), (A-11a6), (A-11a7),(A-11a8), (A-11a9), and (A-11a10). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11a).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only includecompounds which have structural formula (A-11b):

wherein:R3, R4, and R6 are as defined in structural formula (A) and R7 ishydrogen or C1-C3 alkyl. In other embodiments, such compounds arespecifically excluded from structural formula (A).

Structural Formula (A-11b1).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which R3 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b2).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which R4 is hydrogen. Inother embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b3).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which R3 and R4 are hydrogen.In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b4).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is hydrogen, alkyl,

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b5).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b6).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b7).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen,    -   b. R6 is

and

-   -   c. R10 is alkyl.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b8).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b9).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and n is 2.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b10).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

and

-   -   c. R9 and R10, together with the nitrogen atom to which they are        attached, form a heterocycle containing 1, 2, 3, or 4        heteroatoms selected from N, O, and S, optionally substituted        with 1, 2, or 3 substituents selected independently from R11,        wherein R11 is as defined in structural formula (A).

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Structural Formula (A-11b11).

Some embodiments specifically include and some embodiments only includecompounds of structural formula (A-11b) in which

-   -   a. R3 and R4 are hydrogen and    -   b. R6 is

-   -   c. R9 is alkyl or alkoxylalkyl, and    -   d. R10 is hydrogen.

In other embodiments, such compounds are specifically excluded fromstructural formulae (A) and/or (A-11b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b1) and (2) compounds of any ofstructural formulae (A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b6),(A-11b7), (A-11b8), (A-11b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b1) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b6), (A-11b7), (A-11b8),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b2) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b3), (A-11b4), (A-11b5), (A-11b6),(A-11b7), (A-11b8), (A-11b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b2) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b3), (A-11b4), (A-11b5), (A-11b6), (A-11b7), (A-11b8),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b3) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b2), (A-11b4), (A-11b5), (A-11b6),(A-11b7), (A-11b8), (A-11b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b3) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b4), (A-11b5), (A-11b6), (A-11b7), (A-11b8),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b4) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b5), (A-11b6),(A-11b7), (A-11b8), (A-11b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b4) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b5), (A-11b6), (A-11b7), (A-11b8),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b5) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b6),(A-11b7), (A-11b8), (A-11b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b5) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b6), (A-11b7), (A-11b8),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b6) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5),(A-11b7), (A-11b8), (A-11b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b6) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b7), (A-11b8),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b7) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5),(A-11b6), (A-11b8), (A-11 b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b7) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b6), (A-11b8),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b8) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5),(A-11b6), (A-11b7), (A-11b9), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b8) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b6), (A-11b7),(A-11b9), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b9) and (2) compounds of any ofstructural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5),(A-11b6), (A-11b7), (A-11b8), (A-11b10), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b9) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b6), (A-11b7),(A-11b8), (A-11b10), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b10) and (2) compounds of anyof structural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5),(A-11b6), (A-11b7), (A-11b8), (A-11b9), and (A-11b11). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b10) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b6), (A-11b7),(A-11b8), (A-11b9), and (A-11b11). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b11) and (2) compounds of anyof structural formulae (A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5),(A-11b6), (A-11b7), (A-11b8), (A-11b9), and (A-11b10). In otherembodiments, such compounds are specifically excluded from structuralformulae (A) and/or (A-11b). Each possible combination is specificallycontemplated as if set forth explicitly herein.

Some embodiments specifically include and some embodiments only include(1) compounds of structural formula (A-11b11) and (2) compounds of up to10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of structural formulae(A-11b1), (A-11b2), (A-11b3), (A-11b4), (A-11b5), (A-11b6), (A-11b7),(A-11b8), (A-11b9), and (A-11b10). In other embodiments, such compoundsare specifically excluded from structural formulae (A) and/or (A-11b).Each possible combination is specifically contemplated as if set forthexplicitly herein.

Table 1 provides examples of compounds encompassed by one or more of thestructural formulae described above. The average IC₅₀ and EC₅₀ weredetermined as described in the Examples below. These and other compoundswithin the scope of the formulae described above can be synthesizedaccording to general methods known in the art and as described in thespecific Examples, below.

TABLE 1 IC50_av EC50_av Compound Structure (μM) (μM) 1

<0.1 <10 2

<0.1 <10 3

<0.1 <10 4

<0.1 >10 5

<0.1 <10 6

<0.1 <10 7

<0.1 >10 8

>10 >10 9

<1 <10 10

<0.1 <10 11

<0.1 <10 12

<0.1 <10 13

<0.1 <10 14

<0.1 <10 15

nd <10 16

<0.1 >10 17

<0.1 <10 18

<1 <10 19

>1 <10 20

<1 >10 21

<0.1 >10 22

<0.1 <10 23

<1 <10 24

<0.1 <10 25

<0.1 <10 26

<1 <10 27

<0.1 <10 28

<10 >10 29

>10 nd 30

>10 nd 31

>10 nd 32

<10 nd 33

<10 >10 34

<10 >10 35

<0.1 >10 36

<1 >10 37

<0.1 >10 38

<0.1 >10 39

<0.1 >10 40

<1 >10 41

<1 <10 42

<1 <10 43

<1 <10 44

<1 <10 45

<1 <10 46

<0.1 <10 47

<0.1 >10 48

<0.1 <10 49

<0.1 >10 50

<0.1 <10 51

<0.1 <10 52

<0.1 >10 53

<0.1 >10 54

<0.1 >10 55

<0.1 >10 56

<0.1 >10 57

<0.1 >10 58

<1 >10 59

<1 >10 60

<0.1 >10 61

<0.1 >10 62

<0.1 >10 63

<0.1 >10 64

<0.1 >10 65

<0.1 <10 66

67

<1 >10 68

<0.1 <10 69

<0.1 <10 70

<0.1 >10 71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

>10 89

90

91

92

93

>10 94

>10 95

96

97

98

99

100

101

102

103

104

105

106

<0.1 <10 107

<0.1 <10 108

<0.1 <10 109

<0.1 <10 110

<1 <10 111

<0.1 <10 112

<0.1 <10 113

<0.1 <10 114

<1 <10 115

<1 <10 116

<0.1 <10 117

<1 <10 118

<0.1 <10 119

<1 >10 120

<1 <10 121

<0.1 <10 122

ND <10 123

ND <10 124

ND <10 125

ND <10 126

ND <10 127

<0.1 <10 128

<1 >10 129

<0.1 <10 130

<0.1 <10 131

<0.1 <10 132

<0.1 <10 133

<0.1 <10 134

ND <10 135

ND <10 136

<1 <10 137

<0.1 <10 138

<1 >10 139

<0.1 <10 140

<1 >10 141

<0.1 <10 142

<0.1 <10 143

<1 <10 144

ND >10 145

ND <10 146

<0.1 <10 147

<0.1 >10 148

<0.1 >10 149

<1 <10 150

<1 >10 151

<1 >10 152

<1 <10 153

<0.1 <10 154

<0.1 <10 155

<1 <10 156

<1 >10 157

<1 >10 158

ND <10 159

ND <10 160

ND <10 161

ND <10 162

ND <10 163

ND <10 164

ND >10 165

ND <10 166

<1 <10 167

<0.1 <10 168

<0.1 <10 169

<0.1 <10 170

<1 <10 171

<0.1 <10 172

<0.1 <10 173

<0.1 <10 174

<0.1 <10 175

<1 >10 176

<0.1 <10 177

<0.1 <10 178

ND <10 179

<1 <10 180

<0.1 <10 181

<0.1 <10 182

<0.1 <10 183

ND <10 184

<0.1 <10 185

<0.1 >10 186

<1 >10 187

ND <10 188

ND <10 189

ND <10 190

ND <10 191

ND <10 192

<1 <10 193

<0.1 <10 194

<0.1 <10 195

ND <10 196

<0.1 <10 197

<1 <10 198

>1 <10 199

<0.1 >10 200

<0.1 >10 201

<0.1 <10 202

ND >10 203

ND <10 204

ND >10 205

ND 10 206

ND 10 207

>10 208

>10 209

<10 210

>10 211

>10 212

>10 213

>10 214

>10 215

<10 216

<10 217

<10 218

>10 219

>10 220

<10 221

>10 222

<10 223

<10 224

>10 225

>10 226

<10 227

<10 228

<10 229

>10 230

>10 231

>10 232

>10 233

<10 234

>10 235

>10 236

>10 237

>10 238

>10 239

>10 240

>10 241

>10 242

>10 243

>10 244

>10 245

<10 246

>10 247

>10 248

>10 249

>10 250

>10 251

>10 252

>10 253

<10 254

>10 255

<10 256

>10 257

>10 258

>10 259

>10 260

>10 261

<10 262

<10 263

>10 264

>10 265

>10 266

<10 267

>10 268

>10 269

>10 270

ND 271

<10 272

ND 273

>10 274

>10 275

>10 276

>10 277

>10 278

>10 279

>10 280

>10 281

>10 282

>10 283

>10 284

>10 285

<10 286

<10 287

ND 288

ND 289

ND 290

ND 291

ND 292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

IRE-1α inhibitor compounds include both the free forms andpharmaceutically acceptable salts of pharmaceutically usablestereoisomers, E/Z isomers, enantiomers, racemates, diastereomers,hydrates, and solvates. Some of the specific IRE-1α inhibitor compoundsdescribed herein are the protonated salts of amine compounds. The term“free form” refers to the amine compounds in non-salt form. Theencompassed pharmaceutically acceptable salts not only include the saltsdescribed for the specific compounds disclosed herein, but also all thetypical pharmaceutically acceptable salts of the free form of IRE-1αinhibitor compounds and prodrugs thereof.

The free form of the specific salt compounds described may be isolatedusing techniques known in the art. For example, the free form may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous NaOH, potassium carbonate, ammonia andsodium bicarbonate. The free forms may differ from their respective saltforms somewhat in certain physical properties, such as solubility inpolar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms.

Pharmaceutically acceptable salts of the disclosed IRE-1α inhibitorcompounds can be synthesized which contain a basic or acidic moiety byconventional chemical methods. Generally, the salts of the basiccompounds are prepared either by ion exchange chromatography or byreacting the free base with stoichiometric amounts or with an excess ofthe desired salt-forming inorganic or organic acid in a suitable solventor various combinations of solvents. Similarly, the salts of the acidiccompounds are formed by reactions with the appropriate inorganic ororganic base.

Pharmaceutically acceptable salts of IRE-1α inhibitor compounds includethe conventional non-toxic salts of the compounds as formed by reactinga basic compound with an inorganic or organic acid. For example,conventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like, as well as salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric,toluenesulfonic, benzenesulfonic, methanesulfonic, ethane disulfonic,oxalic, isethionic, trifluoroacetic and the like.

When an IRE-1α inhibitor compound is acidic, suitable pharmaceuticallyacceptable salts include salts prepared form pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases. Saltsderived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc and the like. Particular salts are the ammonium,calcium, magnesium, potassium and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine tripropylamine, tromethamineand the like. The preparation of the pharmaceutically acceptable saltsdescribed above and other typical pharmaceutically acceptable salts ismore fully described by Berg et al., “Pharmaceutical Salts,” J. Pharm.Sci., 1977:66:1-19.

Some IRE-1α compounds or prodrugs are potentially internal salts orzwitterions, because under physiological conditions a deprotonatedacidic moiety in the compound, such as a carboxyl group, may be anionic,and this electronic charge might then be balanced off internally againstthe cationic charge of a protonated or alkylated basic moiety, such as aquaternary nitrogen atom.

IRE-1α inhibitor compounds or prodrugs thereof may have asymmetriccenters, chiral axes, and chiral planes (as described in: E. L. Elieland S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons,New York, 1994, pages 1119-1190), and may occur as racemates, racemicmixtures, and as individual diastereomers, with all possible isomers andmixtures thereof, including optical isomers, being included.

An IRE-1α inhibitor compound or prodrug thereof may be of such a naturethat its constituent atoms are capable of being arranged spatially intwo or more ways, despite having identical bonds. As a consequence, thiscompound exists in the form of stereoisomers. Cis/trans isomerism isonly one type of stereoisomerism. If the stereoisomers are image andmirror image which cannot be superimposed, they are enantiomers whichhave chirality or handedness since one or more asymmetric carbon atomsare present in the structure forming them. Enantiomers are opticallyactive and therefore distinguishable since they rotate the plane ofpolarized light to an equal extent, but in opposite directions.

“Solvates” are adductions of inert solvent molecules onto the compoundswhich form owing to their mutual attractive force. Solvates are, forexample, monohydrates, dihydrates or alcoholates.

If two or more asymmetric carbon atoms are present in an IRE-1αcompound, two possible configurations exist at each of these carbonatoms. If two asymmetric carbon atoms are present, four possiblestereoisomers exist, for example. Furthermore, these four possiblestereoisomers can be divided into six possible pairs of stereoisomersthat differ from each other. In order for a pair of molecules with morethan one asymmetric carbon to be enantiomers, they must have differentconfigurations at each asymmetric carbon. Those pairs that do not behaveas enantiomers have a different stereochemical relationship, which isknown as a diastereomeric relationship. Stereoisomers that are notenantiomers are known as diastereoisomers, or, more frequently,diastereomers.

IRE-1α inhibitor compounds thus include stereoisomers, and, if these areenantiomers, the individual enantiomers, racemic mixtures of theseenantiomers, and artificial, i.e. synthetic, mixtures comprisingproportions of these enantiomers which are different from theproportions of these enantiomers observed in a racemic mixture. If anIRE-1α inhibitor compound has stereoisomers that are diastereomers, thiscompound includes the individual diastereomers as well as mixtures ofany two or more of these diastereomers in any desired proportions.

The specific biological effects and/or physical and chemical propertiesof a pair or set of enantiomers of an IRE-1α inhibitor compound—ifpresent—may make it desirable to use these enantiomers in certainratios, for example to form a final therapeutic product. The followingis intended to serve for illustration: if a pair of enantiomers exists,the enantiomers can be used in ratios such as 90% (R)-10% (S), 80%(R)-20% (S), 70% (R)-30% (S), 60% (R)-40% (S), 50% (R)-50% (S), 40%(R)-60% (S), 30% (R)-70% (S), 20% (R)-80% (S), and 10% (R)-90% (S).After evaluation of the properties of the various enantiomers of anIRE-1α inhibitor compound—if they exist—the corresponding amount of oneor more of these enantiomers having certain desired properties whichform the final therapeutic product can be determined in a simple manner.

For IRE-1α inhibitor compounds disclosed herein which may exist astautomers, both tautomeric forms are encompassed by a depictedstructural formula, even though only one tautomeric structure isdepicted. For example, a compound such as that below drawn as the ketotautomer includes the enol tautomer, and vice versa, as well as mixturesthereof.

Prodrugs

A “prodrug” as used herein is a compound that can be metabolized toactive IRE-1α inhibitor compound after administration. For example,IRE-1α inhibitor compounds disclosed herein can be modified, e.g., withalkyl or acyl groups, sugars, or oligopeptides and which are rapidlycleaved in vivo to release the active IRE-1α inhibitor compounds.

Derivatives of the corresponding aromatic alcohols can serve as prodrugsfor aromatic aldehydes because alcohols and aldehydes are metabolicallyinterconvertible, according to the following general scheme:

Scheline, 1972, Xenobiotica, 2, 227-36.

Examples of prodrugs of aldehydes, ketones, alcohols and otherfunctional groups are described in Wermuth et al., 1996, DesigningProdrugs and Bioprecursors I: Carrier Prodrugs. In The Practice ofMedicinal Chemistry, pp. 672-696; and in Wermuth, 1996, “Preparation ofWater-Soluble Compounds by Covalent Attachment of SolubilizingMoieties,” in Wermuth, ed., The Practice of Medicinal Chemistry, pp.756-776. Other general aldehyde derivatives and alcohol derivatives thatcan perform prodrug functions as well as methods for their preparationare described in Cheronis et al., 1965, Semimicro Qualitative OrganicAnalysis, New York: Interscience, pp. 465-518.

Methods of Preparing IRE-1α Inhibitor Compounds and Prodrugs

IRE-1α inhibitor compounds and starting materials for their synthesiscan be prepared by appropriate modification of methods known in the artas described in the literature, for example in standard works such asHouben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag,Stuttgart. Methods may also be found by computer search in The MDL®CrossFire Beilstein database, in which the reaction domain details thepreparation of substances. See also the specific Examples, below.

Pharmaceutical Preparations

Any of the IRE-1α inhibitor compounds and prodrugs disclosed herein canbe formulated as pharmaceuticals using methods well known in the art.Pharmaceutical formulations typically comprise at least one IRE-1αinhibitor compound or prodrug thereof mixed with a carrier, diluted witha diluent, and/or enclosed or encapsulated by an ingestible carrier inthe form of a capsule, sachet, cachet, paper, or other container, or bya disposable container such as an ampoule.

A carrier or diluent can be a solid, semi-solid, or liquid material.Some examples of diluents or carriers which can be employed in thepharmaceutical compositions are lactose, dextrose, sucrose, sorbitol,mannitol, propylene glycol, liquid paraffin, white soft paraffin,kaolin, microcrystalline cellulose, calcium silicate, silicapolyvinylpyrrolidone, cetostearyl alcohol, starch, gum acacia, calciumphosphate, cocoa butter, oil of theobroma, arachis oil, alginates,tragacanth, gelatin, methyl cellulose, polyoxyethylene sorbitanmonolaurate, ethyl lactate, propylhydroxybenzoate, sorbitan trioleate,sorbitan sesquioleate, and oleyl alcohol.

Pharmaceutical compositions can be manufactured by methods well known inthe art, including conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes.

For injection, the IRE-1α inhibitor compounds can be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art. If desired, any of the IRE-1α inhibitorcompounds or prodrugs thereof disclosed herein can be provided in apyrogen-free pharmaceutically acceptable vehicle.

For oral administration, an IRE-1α inhibitor compound or prodrug thereofcan be combined with pharmaceutically acceptable carriers or vehicleswhich enable the IRE-1α inhibitor compound or prodrug thereof to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like. Fillers can be used, such asgelatin, sugars (e.g., lactose, sucrose, mannitol, or sorbitol),cellulose preparations (e.g., maize starch, wheat starch, rice starch,potato starch, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose), and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof, such as sodium alginate.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, an IRE-1α inhibitor compound or prodrug thereof can bedissolved or suspended in a suitable liquid, such as fatty oils, liquidparaffin, or liquid polyethylene glycols. In addition, stabilizers canbe added. All formulations for oral administration preferably are indosages suitable for such administration.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in conventional manners.

For administration by inhalation, pharmaceutical preparations can bedelivered in the form of an aerosol sprays from a pressurized pack or anebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Ifdesired, a valve can be used to deliver a metered amount. Capsules andcartridges of, e.g., gelatin for use in an inhaler or insufflator, canbe formulated containing a powder mix of an IRE-1α inhibitor compound orprodrug thereof and a suitable powder base, such as lactose or starch.

IRE-1α inhibitor compounds or prodrugs thereof can be formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection can be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing, and/or dispersingagents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of an IRE-1α inhibitor compound or prodrug thereof.Additionally, a suspension of an IRE-1α inhibitor compound or prodrugthereof can be prepared as an appropriate oily injection suspension.Suitable lipophilic solvents or vehicles include fatty oils such assesame oil, synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. Aqueous injection suspensions can containsubstances which increase the viscosity of the suspension, such assodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension can also contain suitable stabilizers or agents whichincrease the solubility of an IRE-1α inhibitor compound or prodrugthereof to allow for the preparation of highly concentrated solutions.

Alternatively, an IRE-1α inhibitor compound or prodrug thereof can be inpowder form for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

IRE-1α inhibitor compounds or prodrugs thereof can also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

In addition to the formulations described previously, an IRE-1αinhibitor compound or prodrug thereof can also be formulated as a depotpreparation. Such long-acting formulations can be administered byimplantation (for example, subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, an IRE-1α inhibitor compoundor prodrug thereof can be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to, calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

In addition to the common dosage forms set out above, an IRE-1αinhibitor compound or prodrug thereof can be administered by acontrolled release means and/or delivery device, including ALZET®osmotic pumps (Alza Corporation). Suitable delivery devices aredescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;3,944,064; and 4,008,719.

Methods

IRE-1α inhibitor compounds or prodrugs thereof can be used to inhibitIRE-1α activity (e.g., cleavage of RNA or mRNA, RNA or mRNA splicing).In some embodiments IRE-1a activity (e.g., cleavage of RNA or mRNA, RNAor mRNA splicing) is inhibited in vitro. In other embodiments IRE-1αactivity (e.g., cleavage of RNA or mRNA, RNA or mRNA splicing) isinhibited in vivo.

IRE-1α inhibitor compounds or prodrugs thereof can be used to prepareformulations or medicaments for inhibiting tumor cell growth and fortreating the disorders disclosed below. IRE-1α inhibitor compounds orprodrugs thereof can be administered to a patient, preferably a humanpatient, in pharmaceutical preparations as disclosed above, preferablywith a pyrogen-free pharmaceutically acceptable vehicle, at doseseffective to treat or ameliorate a symptom of a disorder associated withthe unfolded protein response. IRE-1α inhibitor compounds and prodrugsthereof can be used to treat patient populations which are not entirelycoincident with those most commonly receiving treatment for disordersassociated with the unfolded protein response (e.g., cancer therapies ortherapies for autoimmune disorders). For example, IRE-1α inhibitorcompounds and prodrugs thereof can be administered to patients at theearliest stages of these conditions, even those to whom traditionaltherapies are commonly not offered.

Disorders Associated with UPR

A fine balance exists between a cell's life and death depending on howprotein folding stress is managed by the cell (proteostasis). Imbalancesin proteostasis lead to many metabolic, oncological, neurodegenerative,inflammatory, cardiovascular disorders and infectious disease (Balch etal., Science 319, 916, 2008). The UPR relates specifically to theproteostasis of the endoplasmic reticulum where all secreted andmembrane proteins are translated, folded and processed for delivery totheir individual site of action. Therefore, activation of the UPRenhances protein folding in the ER allowing the cell to survive. Ifprotein folding stress is not managed in the ER, the cells will initiateapoptosis.

Protein folding stress may be a natural hallmark of the type of cell forexample insulin secreting β-islet cells or antibody secreting plasmacells. In both cases, the cell has fine tuned the machinery to deal withthe stress by activating the UPR. Depending on the disease type, it maybe therapeutically beneficial to induce or inhibit the UPR. For example,in type II diabetes or Alzheimer's disease, it may be therapeuticallybeneficial to activate the UPR in such a way where β-islet cells survivethe stress of over producing insulin or neurons survive the apoptoticeffects due to unfolded aggregates of β-amyloid protein. Diseases suchas cancer, inflammation, and viral infection may be therapeuticallymodulated by inhibition of the UPR. In these types of conditions,cellular survival due to corruption of the UPR may be impacted. Proteinfolding in the ER is negatively impacted by such conditions in the tumormicroenvironment as hypoxia, glucose starvation, amino acid deprivation,acidosis and mutant malfolded and oncogenic proteins. Additionallychemo-, bio-, and radiotherapy can lead to protein folding stress. Itmay be possible to induce apoptosis in these conditions by inhibitingthe anti-apoptotic effects of the UPR. Myeloma derived from neoplasticantibody secreting plasma cells provides an example of a condition inwhich this approach can be applied.

Lastly, enveloped viruses must use and corrupt this system to ensureproduction of progeny from infected cells. Viruses often produce vastquantities of viral membrane glycoproteins which are folded and modifiedin the ER. Therefore, activation of the UPR by the virus for thispurpose as a survival mechanism is entirely conceivable. It is thereforelogical that inhibition of the UPR during viral infection can impact theoutcome of the disease in a beneficial way.

Only specialized secretory cells and diseased cells activate the UPR fortheir own benefit. Most cells are not under such protein folding stressand therefore would not be impacted by a UPR inhibitor. Thus, “disordersassociated with the UPR” as used herein means conditions for whichpathogenesis can be advantageously impacted by inhibition of the UPR. Invarious embodiments such inhibition of the UPR is accomplished throughinhibition of IRE-1α.

In some embodiments the IRE-1α inhibitor compounds or prodrugs thereofare useful to treat or ameliorate a symptom of a B cell autoimmunedisease, certain cancers, and infections of enveloped viruses that usethe endoplasmic reticulum as a viral factory for expressing viralsurface and spike proteins for budding and infection. IRE-1α inhibitorsand prodrugs thereof can be used as single agents or in combinationtherapies, as described below.

B cell autoimmune diseases which can be treated include, but are notlimited to, Addison's disease, antiphospholipid syndrome, aplasticanemia, autoimmune hemolytic anemias, autoimmune hepatitis, autoimmunehypophysitis, autoimmune lymphoproliferative disorders, autoimmunemyocarditis, Churg-Strauss syndrome, epidermolysis bullosa acquisita,giant cell arteritis, Goodpasture's syndrome, Graves' disease,Guillain-Barré syndrome, Hashimoto's thyroiditis, idiopathicthrombocytopenic purpura, IgA nephropathy, myasthenia gravis, pemphigusfoliaceous, pemphigus vulgaris, polyarteritis nodosa,polymyositis/dermatomyositis, rheumatoid arthritis, scleroderma,Sjögren's syndrome, systemic lupus erythematosus, Takayasu's arteritis,and Wegener's granulomatosis.

Cancers which can be treated include solid tumors, such as tumors of thebreast, bone, prostate, lung, adrenal gland (e.g., adrenocorticaltumors), bile duct, bladder, bronchus, nervous tissue (includingneuronal and glial tumors), gall bladder, stomach, salivary gland,esophagus, small intestine, cervix, colon, rectum, liver, ovary,pancreas, pituitary adenomas, and secretory adenomas. Methods areparticularly useful for treating drug- or radiation-resistant solidtumors.

Cancers of the blood (e.g., lymphomas and leukemias) also can be treatedincluding, but not limited to, multiple myeloma, Hodgkin's lymphoma,non-Hodgkin's lymphomas (e.g., cutaneous T cell lymphomas such as Sezarysyndrome and Mycosis fungoides, diffuse large cell lymphoma, HTLV-1associated T cell lymphoma, nodal peripheral T cell lymphoma, extranodalperipheral T cell lymphoma, central nervous system lymphoma, andAIDS-related lymphoma). Leukemias include acute and chronic types ofboth lymphocytic and myelogenous leukemia (e.g., acute lymphocytic orlymphoblastic leukemia, acute myelogenous leukemia, acute myeloidleukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, Tcell prolymphocytic leukemia, adult T cell leukemia, and hairy cellleukemia). Monoclonal gammopathy of undetermined significance (MGUS),the precursor of myeloma, also can be treated.

Viral infections which can be treated include infections of envelopedviruses which use the unfolded protein response pathway when theyreplicate and form infectious progeny (e.g., measles, pox viruses,Ebola, etc.). Infections also include those of Epstein Barr virus (EBV),cytomegalovirus (CMV), Flaviviruses (e.g., Japanese Encephalitis Virusand West Nile Virus), and Hepatitis C virus (HCV).

Combination Therapies

Various types of physiological stress induce the unfolded proteinresponse including, but not limited to, hypoxia, nutrient starvation,acidosis, and genetic damage resulting in mutant or over-expressedmisfolded proteins (oncogenic stress). One or more of these conditionsare manifest in cancer cells, which may in part be mediated by themicroenvironment of the tumor. It is likely the cytoprotective arm ofthe unfolded protein response (UPR) plays an anti-apoptotic role intumor survival. In addition, bio- and chemotherapeutic drugs and thermaland radiation treatments may further impact the protein folding anddegradation cycle in the ER thereby inducing the UPR as a protectiveresistance mechanism. Patients succumb to cancer because either thetumor is resistant to conventional therapies, or returns in a resistantform after an initial response to treatment and, therefore, newtreatments and treatment combinations are needed.

Angiogenesis inhibitors block tumor growth by inhibiting new bloodvessel formation, a process that would enhance the stress effects of thetumor microenvironment. A promising approach to further reduce tumorburden would be to administer anti-angiogenesis agents in combinationwith IRE-1α/XBP-1 inhibitors to obtain a similar effect as thatdemonstrated by RNAi knockdown of GRP78, the major chaperone of the ERand target of XBP-1s (Dong et al., Cancer Res. 2007 Jul. 15;67(2):6700-7). In addition, IRE-1α itself regulates angiogensis byinfluencing the expression of VEGF.

In some embodiments an IRE-1α inhibitor compound or prodrug thereof isadministered in combination with a therapeutic agent that induces orup-regulates IRE-1α expression (e.g., Hsp90 and or HDAC inhibitors, bothof which induce IRE-1α activation and XBP-1 splicing) or a therapeuticagent which is less effective when IRE-1α is expressed (e.g., 17-AAG(TANESPIMYCIN® and suberoylanilide hydroxamic acid (SAHA)).

In some embodiments an IRE-1α inhibitor compound or prodrug thereof isadministered in combination with one or more cancer therapies. Thesetherapies include treatments such as radiation therapy or thermaltreatment (heat shock) as well as administration of therapeutic agents,such as chemotherapeutic agents and biotherapeutic agents, as describedbelow. Such therapies can be administered separately or together withthe IRE-1α inhibitor compound or prodrug, e.g., the one or moretreatments can independently be administered at essentially the sametime as the IRE-1α inhibitor compound or prodrug or can be administeredeither before or after the IRE-1α inhibitor compound.

Cancer therapeutic agents which can be used according to variousembodiments include, but are not limited to, agents in the followingcategories (which may overlap):

-   -   a. proteasome inhibitors, such as bortezomib        ([(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic        acid; MG-341; VELCADE®), MG-132        (N-[(phenylmethoxy)carbonyl]-L-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-L-leucinamide);    -   b. cytotoxic anticancer therapeutics, such as:        -   i. pyrimidine analogs (e.g., 5-fluorouracil, floxuridine,            capecitabine, gemcitabine and cytarabine); and purine            analogs,        -   ii. alkylating agents such as nitrogen mustards (e.g.,            mechlorethamine, cyclophosphamide and analogs, melphalan,            chlorambucil), ethylenimines and methylmelamines (e.g.,            hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan,            nitrosoureas (e.g., carmustine (BCNU) and analogs,            streptozocin), trazenes—dacarbazinine (DTIC);        -   iii. microtubule disrupters such as taxane (paclitaxel,            docetaxel), vincristin, vinblastin, nocodazole, epothilones            and navelbine, and epidipodophyllotoxins (e.g., teniposide);            natural products such as vinca alkaloids (e.g., vinblastine,            vincristine, and vinorelbine);        -   iv. DNA damaging agents, such as actinomycin, amsacrine,            anthracyclines, bleomycin, busulfan, camptothecin,            carboplatin, chlorambucil, cisplatin, cyclophosphamide,            Cytoxan, dactinomycin, daunorubicin, docetaxel, doxorubicin,            epirubicin, hexamethylmelamineoxaliplatin, iphosphamide,            melphalan, merchlorethamine, mitomycin, mitoxantrone,            nitrosourea, paclitaxel, plicamycin, procarbazine,            teniposide, triethylenethiophosphoramide and etoposide (VP            16); and platinum coordination complexes (e.g., cisplatin,            carboplatin), procarbazine, hydroxyurea, mitotane,            aminoglutethimide;    -   c. antibiotics, such as dactinomycin (actinomycin D),        daunorubicin, doxorubicin (adriamycin), idarubicin,        anthracyclines, mitoxantrone, bleomycins, plicamycin        (mithramycin) and mitomycin;    -   d. folate antagonists and related inhibitors (e.g.,        mercaptopurine, thioguanine, pentostatin and        2-chlorodeoxyadenosine [cladribine]); folic acid analogs (e.g.,        methotrexate)    -   e. hormones, hormone analogs (e.g., estrogen, tamoxifen,        goserelin, bicalutamide, nilutamide);    -   f. aromatase inhibitors (e.g., letrozole, anastrozole);    -   g. fibrinolytic agents (such as tissue plasminogen activator,        streptokinase and urokinase), aspirin, COX-2 inhibitors,        dipyridamole, ticlopidine, clopidogrel, abciximab;    -   h. antimigratory agents;    -   i. antisecretory agents (e.g., breveldin); immunosuppressives        (e.g., cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin),        azathioprine, mycophenolate mofetil);    -   j. anti-angiogenic compounds (e.g., TNP-470, genistein, Sutent,        Vatalinib) and growth factor inhibitors (e.g., vascular        endothelial growth factor (VEGF) inhibitors, fibroblast growth        factor (FGF) inhibitors, epidermal growth factor (EGF)        inhibitors); and multi-kinase inhibitors (e.g., lestaurtinib);    -   k. antibodies (e.g., trastuzumab (HERCEPTIN®), AVASTIN®,        ERBITUX®);    -   l. cell cycle inhibitors and differentiation inducers (e.g.,        tretinoin);    -   m. mTOR (mammalian target of rapamycin) inhibitors (e.g.,        everolimus, sirolimus);    -   n. topoisomerase inhibitors (e.g., doxorubicin (adriamycin),        amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide,        epirubicin, etoposide, idarubicin, irinotecan (CPT-11) and        mitoxantrone, topotecan, irinotecan);    -   o. corticosteroids (e.g., cortisone, dexamethasone,        hydrocortisone, methylpednisolone, prednisone, and prenisolone);    -   p. HSP90 inhibitors (e.g., 17-AAG)    -   q. mitochondrial dysfunction inducers (e.g., 2-deoxyglucose,        dichloroacetic acid);    -   r. caspase activators; and    -   s. chromatin disrupters.

In some embodiments the cancer therapeutic agent is selected from thegroup consisting of alemtuzumab, aminoglutethimide, amsacrine,anastrozole, asparaginase, beg, bevacizumab, bicalutamide, bleomycin,bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin,carmustine, CeaVac, cetuximab, chlorambucil, cisplatin, cladribine,clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine,dacarbazine, daclizumab, dactinomycin, daunorubicin, dienestrol,diethylstilbestrol, docetaxel, doxorubicin, edrecolomab, epirubicin,epratuzumab, erlotinib, estradiol, estramustine, etoposide, exemestane,filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone,flutamide, gemcitabine, gemtuzumab, genistein, goserelin, huJ591,hydroxyurea, ibritumomab, idarubicin, ifosfamide, IGN-101, imatinib,interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide,levamisole, lintuzumab, lomustine, MDX-210, mechlorethamine,medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, mitumomab, nilutamide,nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate,pentostatin, pertuzumab, plicamycin, porfimer, procarbazine,raltitrexed, rituximab, streptozocin, sunitinib, suramin, tamoxifen,temozolomide, teniposide, testosterone, thalidomide, thioguanine,thiotepa, titanocene dichloride, topotecan, tositumomab, trastuzumab,tretinoin, vatalanib, vinblastine, vincristine, vindesine, andvinorelbine.

Inhibition of IRE-1α Dependent Decay of Membrane Associated mRNAs (RIDD)Pathway Using IRE-1α Inhibitors

Inositol requiring enzyme-1 (IRE-1α) is the most highly conservedsignaling node of the unfolded protein response (UPR) and represents apotential therapeutic target for a number of diseases associated withendoplasmic reticulum (ER) stress. IRE-1α activates the XBP-1transcription factor by site specific cleavage of two hairpin loopswithin its mRNA promoting its nonconventional splicing and alternativetranslation. In addition, the endoribonuclease of IRE-1α is required forthe cleavage and degradation of certain mRNAs coding for primarilysecreted and transmembrane proteins targeted to the ER called IRE-1αdependent mRNA decay (RIDD). However, it had not been known whether thisis a direct activity or the subsequent activation of a secondendoribonuclease. Using IRE-1α specific endoribonuclease inhibitors,Examples 43-46 below demonstrate that this activity is likely directfrom the IRE-1α endoribonuclease and that inhibitors selectivity blockdown-regulation of known targets of the RIDD pathway including but notlimited to CD59 and Blos1. IRE-1α inhibitors therefore be useful totreat or ameliorate a symptom of a neurological disorder, or disordersthat involve overproduction of insulin or inflammation.

Protein folding perturbations resulting in endoplasmic reticulum (ER)stress are thought to play a role in the pathogenesis of diseases asdiverse as neurodegeneration, diabetes and cancer. The unfolded proteinresponse (UPR) coordinates the ability of a cell to respond to ER stressby altering protein translation, folding, and post translationalmodification of all secreted and membrane proteins. Terminally unfoldedproteins are retro-transported to the cytosol by the ER associateddegradation (ERAD) machinery for proteolysis by the proteasome. The ERis also the site of lipid biosynthesis and membrane expansion. Theseactivities are linked physiologically to specialized secretory cells;however, depending on stress levels, the UPR can control cellularsurvival or death via autophagy and apoptosis (Ron & Walter, Nat Rev MolCell Biol. 8(7), 519-29, 2007). Secretion and membrane composition arebalanced by the high caloric demand of these activities against theenergy homeostasis of the cell (Ron & Walter, 2007).

Inositol requiring enzyme 1 (IRE-1α) is the most highly conservedsignaling node of the unfolded protein response (Ron & Walter, 2007). Aunique ER resident transmembrane kinase with a novel C-terminalendoribonuclease domain, IRE-1α is activated in part by thedisassociation of BiP/GRP78 in the presence of unfolded protein in theER lumen (Ron & Walter, 2007). The signal is transduced to the cytosolby the sequential dimerization/multimerization,trans-autophosphorylation and activation of its endoribonuclease(Tirasophon et al., Genes Dev. 14 (21) 2725-36, 2000). The specificactivity of the endoribonuclease is responsible for the unconventionalcytosolic splicing of HAC1 in yeast and excision of the 26 nucleotideintron of the X-box binding protein (XBP-1) transcription factor inmetazoan organisms (Ron & Walter, 2007). In mammalian cells IRE-1α actsin concert with companion UPR signaling molecules PKR-like ER residentkinase (PERK) and ATF6 (Ron & Walter, 2007).

XBP-1 mRNA, a major substrate of the IRE-1α endoribonuclease, is cleavedspecifically at two conserved stem-loop sites. Each site is located 3′to a mirrored guanosine residue in the 7 base loop (Ron & Walter, 2007).The resulting internal fragment, a 26-nt intron, is removed and the twoexon ends are ligated by and unknown mechanism in mammalian cells and bytRNA ligase in yeast (Ron & Walter, 2007). The rejoined mRNA shifts theOpen Reading Frame (ORF) and extends the C-terminal domain of XBP-1 fromamino acid 164 with an alternative 212 amino acid reading frameproducing the active “spliced” transcription factor, XBP-1s, whichregulates a broad range of ER resident chaperones, ER transloconchannels, ERAD components and lipid metabolic enzymes (Ron & Walter,2007). An emerging and important activity of IRE-1α is regulatedIre1-dependent decay (RIDD) of mRNAs encoding ER targeted membrane andsecreted proteins during stress analogous to the less discriminate buttargeted activities of IRE-1α's evolutionary homologue, RNase L (Hollien& Weissman, Science 313(5783) 104-07, 2006). This activity incombination with XBP-1s expression has the potential to alter thesurface composition of stressed cells and the extracellular proteome. Inaddition, it appears to selectively target different mRNAs in differenttypes of cells. Substrates include but are not limited to insulin (Hanet al., Cell 138(3) 562-75, 2009), CD59 (Oikawa et al., Biochem BiophysRes Commun. 360(1) 122-127, 2007), Blos1 (Hollien et al., J Cell Biol.186(3) 323-31, 2009), DGAT2 (Thorpe & Schwarze, Cell Stress Chaperones.15(5) 497-508, 2010) and IRE-1α's own mRNA (Tirasophon et al., 2000).IRE-1α endoribonuclease inhibitors selectively block mRNA degradation byIRE-1α including Blos1, DGAT2 and CD59 and IRE-1α itself.

Example 43 below demonstrates that selective and potent IRE-1αendoribonuclease inhibitors disclosed herein can block the RIDD of mRNAtargets in both unstressed and ER stressed RPMI 8226 myeloma cells.Diseases linked to ER stress include neurodegenerative diseases,diabetes, inflammation and cancer. This has important implications fordisease management.

For example, CD59 is a GPI linked cell surface glycoprotein which asmember of the complement regulatory factor family which includes CD46and CD55. Compliment regulatory factors inhibit complement mediatedlysis of cells by preventing membrane attack complex formation. Downmodulation of CD59 may play a role in many diseases with an immunecomponent, such as Barraquer-Simons Syndrome, asthma, lupuserythematous, glomerulonephritis, various forms of arthritis, autoimmuneheart disease, multiple sclerosis, inflammatory bowel disease, andischemia-reperfusion injuries, autoimmune hemocytopenias and rejectionof transplanted organs (Song, Autoimmunity 39(5) 403-10, 2006;Ruiz-Argüelles & Llorente, Autoimmun Rev. 6(3):155-61, 2007; Arumugam etal., Shock 21(5) 401-06, 2004; Asgari et al., Curr Opin Organ Transplant15(4):486-91, 2010).

Blos1 is a component of endosome-localized Biogenesis ofLysosome-related Organelles Complex-1 (BLOC-1). Alteration of componentsof this complex are associated with schizophrenia. It is conceivablethat down modulation of Blos1 (BLOC1S1) due to IRE-1α activation by ERstress may impact normal synaptic transmission (Ryder & Faundez, SciSignal. 2(93): 66, 2009).

IRE-1α inhibitors disclosed herein (or prodrugs or pharmaceuticallyacceptable salts of IRE-1α inhibitors) can be used to block degradationof Blos1 mRNA, DGAT2 mRNA, CD59 mRNA, and IRE-1α mRNA. In someembodiments, a cell comprising an mRNA selected from the groupconsisting of Blos1 mRNA, DGAT2 mRNA, CD59 mRNA, and IRE-1α mRNA iscontacted with an IRE-1α inhibitor or a prodrug or pharmaceuticallyacceptable salt of an IRE-1α inhibitor. In some embodiments, the cell isin vitro. In other embodiments, the cell is in vivo.

In some embodiments, an IRE-1α inhibitor or a prodrug orpharmaceutically acceptable salt of an IRE-1α inhibitor is administeredto treat Barraquer-Simons Syndrome, asthma, lupus erythematous,glomerulonephritis, various forms of arthritis, autoimmune heartdisease, multiple sclerosis, inflammatory bowel disease, andischemia-reperfusion injuries, autoimmune hemocytopenias and rejectionof transplanted organs.

In some embodiments, an IRE-1α inhibitor or a prodrug orpharmaceutically acceptable salt of an IRE-1α inhibitor is administeredto treat schizophrenia.

Routes of Administration

Pharmaceutical preparations constituting embodiments can be administeredlocally or systemically. Suitable routes of administration include oral,pulmonary, rectal, transmucosal, intestinal, parenteral (includingintramuscular, subcutaneous, intramedullary routes), intranodal,intrathecal, direct intraventricular, intravenous, intraperitoneal,intranasal, intraocular, transdermal, topical, and vaginal routes. Asdescribed in more detail above, dosage forms include, but are notlimited to, tablets, troches, dispersions, suspensions, suppositories,solutions, capsules, creams, patches, minipumps and the like. Targeteddelivery systems also can be used (for example, a liposome coated withtarget-specific antibody).

Dosage

A pharmaceutical composition embodiment comprises at least one activeingredient (an IRE-1α inhibitor compound or prodrug thereof) in atherapeutically effective dose. A “therapeutically effective dose” isthe amount of an IRE-1α inhibitor compound or prodrug thereof which,when administered to a patient over a treatment period, results in ameasurable improvement in survival time and/or quality of life. Suchimprovements include, for example, a delay or halt in the progression ofa cancer, partial or complete regression, reduced severity of one ormore existing symptoms, delay or prevention of the development of one ormore symptoms, and one or more improved laboratory values (including,but not limited to, a biological marker e.g., XBP-1 splicing and downstream targets such as EDEM, VEGF-A, ERdj4). Various methods and assayscan be used to assess whether and to what extent an improvement occurs.

Determination of therapeutically effective doses is well within thecapability of those skilled in the art. A therapeutically effective doseinitially can be estimated from in vitro enzyme assays, cell cultureassays, and/or animal models. For example, a dose can be formulated inan animal model to achieve a circulating concentration range at least asconcentrated as the IC₅₀ as determined in an in vitro enzyme assay or ina cell culture (i.e., the concentration of the test compound whichachieves a half-maximal inhibition of IRE-1α activity). Such informationcan be used to more accurately determine useful doses in humans. See theFDA guidance document “Guidance for Industry and Reviewers Estimatingthe Safe Starting Dose in Clinical Trials for Therapeutics in AdultHealthy Volunteers” (HFA-305), which provides an equation for use incalculating a human equivalent dose (HED) based on in vivo animalstudies.

Appropriate animal models for the relevant diseases are known in theart. See, e.g., Lupus. 1996 October; 5(5b):451-5 (antiphospholipidsyndrome); Blood. 1974 July; 44(1):49-56 (aplastic anemia);Autoimmunity. 2001; 33(5):265-74 (autoimmune hypophysitis); Methods.2007 January; 41(1):118-22 (autoimmune myocarditis); Clin Exp Rheumatol.2003 November-December; 21(6 Suppl 32):S55-63 (Churg-Strauss syndrome,Wegener's granulomatosis); J Clin Invest. 2005 April; 115(5):870-8(epidermolysis bullosa acquisita); Circulation. 2005 Jun. 14;111(23):3135-40. Epub 2005 Jun. 6 (giant cell arteritis; Takayusu'sarteritis); Int J Immunopathol Pharmacol. 2005 October-December;18(5):701-8 (IgA nephropathy); Vet Rec. 1984 May 12; 114(19):479(pemphigus foliaceous); J. Neuroimmunol. 98, 130-35, 1999(polymyositis); Am. J. Pathol. 120, 323-25, 1985 (dermatomyositis);Cell. Mol. Immunol. 2, 461-65, 2005 (myasthenia gravis); ArthritisRheum. 50, 3250-59, 2004 (lupus erythymatosus); Clin. Exp. Immunol. 99,294-302, 1995 (Grave's disease); J. Clin. Invest. 116, 961-973, 2006(rheumatoid arthritis); Exp Mol Pathol. 77, 161-67, 2004 (Hashimoto'sthyroiditis); Rheumatol. 32, 1071-75, 2005 (Sjögren's syndrome); BrainPathol. 12, 420-29, 2002 (Guillain-Barré syndrome); Vet. Pathol. 32,337-45, 1995 (polyarteritis nodosa); Immunol. Invest. 3, 47-61, 2006(pemphigus vulgaris); Arch. Dermatol. Res. 297, 333-44, 2006(scleroderma); J. Exp. Med. 191, 899-906, 2000 (Goodpasture's syndrome);Clin. Exp. Immunol. 99, 294-302, 1995 (Grave's disease); J. Clin.Invest. 91, 1507-15, 1993 (membranous nephropathy); J. Immunol. 169,4889-96, 2002 (autoimmune hepatitis); Surgery 128, 999-1006, 2000(Addison's disease); Eur. J. Immunol. 32, 1147-56, 2002 (autoimmunehemolytic anemia); and Haematologica 88, 679-87, 2003 (autoimmunethrombocytopenic purpura).

LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population) can be determined bystandard pharmaceutical procedures in cell cultures and/or experimentalanimals. Data obtained from cell culture assays or animal studies can beused to determine initial human doses. As is known in the art, thedosage may vary depending upon the dosage form and route ofadministration used.

Usual dosages for systemic administration to a human patient range from1 μg/kg to 100 mg/kg (e.g., 1-10 μg/kg, 20-80 μg/kg, 5-50 μg/kg, 75-150μg/kg, 100-500 μg/kg, 250-750 μg/kg, 500-1000 μg/kg, 1-10 mg/kg, 5-50mg/kg, 25-75 mg/kg, 50-100 mg/kg, 5 mg/kg, 20 mg/kg, or 50 mg/kg). Insome embodiments, the treatment schedule can require that a plasmaconcentration of an IRE-1α inhibitor compound be maintained for a periodof time (e.g., several days or a week) and then allowed to decay byceasing administration for a period of time (e.g., 1, 2, 3, or 4 weeks).The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of thedisorder, the manner of administration and the judgment of theprescribing physician.

The following specific examples are provided for purposes ofillustration only and are not intended to limit the scope of the subjectmatter described above.

EXAMPLES

The analytical LC/MS method used in Examples 1-20 employed an Agilent1200 with Variable Wavelength detector extracted at 220 nm and Agilent6140 Single quadrupole mass spectrometer. The HPLC column was a ZorbaxSB-C18, 3.5 μm, 2.1 mm×30 mm, maintained at 40° C. The HPLC Gradient was0.4 mL/min, 95:5:0.1 water:acetonitrile:formic acid for 0.1 min then to5:95:0.1 water:acetonitrile:formic acid in 3.9 min, maintaining for 0.5min.

Example 1 7-Hydroxy-1,2,3,4-tetrahydro-isoquinoline-6-carbaldehydehydrobromide

To a stirred suspension of7-methoxy-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde hydrochloride(91 mg, 0.40 mmol) in anhydrous CH₂Cl₂ (5 mL) boron tribromide (0.42 g,1.68 mmol) was added under argon at −78° C. The reaction was stirred for1 h, allowed to warm to room temperature and stirred for 2 h. Afteraddition of isopropanol and diethyl ether the precipitated product wascollected and washed with ether. In this manner the title compound (79mg, 0.31 mmol, 77.5%) was obtained as a pink powder. LCMS/BB_LCMS01(+)/:M+1=178, Rt: 1.331 min.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1H), 10.23 (s, 1H), 9.07 (br.s., 2H), 7.52 (s, 1H), 6.84 (s, 1H), 4.30 (s, 2H), 3.34-3.40 (m, 2H),2.95 (t, J=6.3 Hz, 2H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 1-1 5-3

BB_LCMS01(+) 178 1.331  99 98 1-2 5-1

BB_LCMS01(+) 178 0.389 100 95 1-3 5-2

BB_LCMS02(+) 178 1.228  96 96

Example 26-Hydroxy-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

To a solution of6-methoxy-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde(62 mg, 0.21 mmol) in dichloromethane (5 mL) stirred under argon at −78°C. was added boron tribromide (0.12 mL, 0.31 g, 1.25 mmol). The reactionwas stirred for 1 h, allowed to warm to room temperature and stirred for2 h. The reaction was quenched by addition of methanol (2 mL) at −78° C.and the mixture was stirred for 1 h. After warming to room temperature,ethyl acetate (3 mL) and diethyl ether (30 mL) were added, uponscratching the product started to precipitate. The mixture was allowedto stand refrigerated overnight, the product was collected, washed withethyl acetate and dried over P₂O₅ to give the title compound (48 mg,0.13 mmol, 61.9%) as a beige powder.

LCMS/BB_LCMS01(+)/: M+1=283, Rt: 2.668 min.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.16 (br. s., 1H), 10.42 (s, 1H), 8.97(s, 1H), 8.91 (dd, J=5.4, 1.1 Hz, 1H), 8.42 (br. s., 1H), 7.94 (dd,J=7.9, 5.6 Hz, 1H), 7.33 (br. s., 1H), 6.87 (br. s., 1H), 4.63 (br. s.,2H), 3.55 (br. s., 2H), 3.21 (br. s., 2H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 2-1   6-1

BB_LCMS01(+) 283 2.668  94 92 2-2   6-2

BB_LCMS01(+) 318 3.624  99 98 2-3   6-3

BB_LCMS01(+) 318 3.572 89 + 9 = 98 98 2-4   6-4

BB_LCMS01(+) 283 2.613  94 95 2-5   6-5

BB_LCMS01(+) 318.1 3.595 100 98 2-6   6-6

BB_LCMS01(+) 283.1 2.643  96 96 2-7   7-1

BB_LCMS01(+) 332 1.189  99 98 2-8   7-2

BB_LCMS01(+) 318 1.967  95 95 2-9   7-3

BB_LCMS01(+) 318.1 1.917  97 98 2-10  7-4

BB_LCMS01(+) 332.2 1.176  96 98 2-11  8-1

BB_LCMS01(+) 334 2.185  96 93 2-12  8-2

BB_LCMS01(+) 304 2.202  94 93 2-13  8-3

BB_LCMS01(+) 334 2.188  99 98 2-14  8-4

BB_LCMS01(+) 304 2.117  96 92 2-15  9-1

BB_LCMS01(+) 268 2.326 100 98 2-16  9-2

BB_LCMS01(+) 268 2.333  93 90 2-17  9-3

BB_LCMS01(+) 268.1 2.317  96 98 2-18 10-1

BB_LCMS01(+) 388 3.033  94 98 2-19 10-2

BB_LCMS01(+) 431 2.527  95 98 2-20 10-3

BB_LCMS01(+) 415 2.536  92 92  2-21* 10-4

BB_LCMS01(+) 401 2.514  91 95 2-22 10-5

BB_LCMS01(+) 401 2.465  92 95 2-23 10-6

BB_LCMS01(+) 387 2.516  94 95 2-24 10-7

BB_LCMS01(+) 401 2.440  94 95 2-25 10-8

BB_LCMS01(+) 387 2.476  91 92 2-26 11-1

BB_LCMS01(+) 297 3.075  99 95 2-27 12-1

BB_LCMS01(+) 387 2.441  91 90 *During O-demethylation the N-Bocprotecting group of the precursor was also removed.

Example 36-Hydroxy-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde

To a stirred suspension of6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde hydrobromide(129 mg, 0.5 mmol) and nicotinoyl chloride hydrochloride (107 mg, 0.6mmol) in 1,2-dichloroethane (6 mL), ethyldiisopropylamine (259 μL, 194mg, 1.5 mmol) was added and the mixture was stirred at room temperaturefor 3 h. After dilution with 1,2-dichloroethane (30 mL) the mixture waswashed with water (3×5 mL). After drying over MgSO₄ and concentrationthe title compound (99 mg, 0.35 mmol, 70%) was obtained.

LCMS/BB_LCMS01(−)/: M+1=281, Rt: 2.592 min.

¹H NMR (400 MHz, DMSO-d₆) δ salt, 2 sets of signals A and B in ratio of55:45 ppm 10.58 (br. s., 1H, A+B), 10.20 (br. s., 0.55H, A), 10.12 (br.s., 0.45H, B), 8.67 (br. s., 2H, A+B), 7.88 (br. s., 1H, A+B), 7.57 (br.s., 0.55H, A), 7.49 (dd, J=7.8, 4.8 Hz, 1H, A+B), 7.36 (br. s., 0.45H,B), 6.81 (s, 1H, A+B), 4.73 (br. s., 1.1H, A), 4.54 (br. s., 0.9H, B),3.82 (br. s., 0.9H, B), 3.53 (br. s., 1.1H, A), 2.89 (br. s., 2H, A+B).

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 3-1 1-2

BB_LCMS01(−) 281 2.592 100 98

Example 46-Hydroxy-2-[3-(4-methyl-piperazin-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde

To a stirred mixture of6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde hydrobromide(82 mg, 0.46 mmol) and triethylamine (322 μL, 234 mg, 2.3 mmol) inanhydrous tetrahydrofuran (2 mL), 3-(4-methyl-piperazin-1-yl)-propionicacid (80 mg, 0.46 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimidehydrochloride (98 mg, 0.51 mmol) and 1-hydroxybenzotriazole (69 mg, 0.51mmol) were added in the above order and the mixture was stirred at roomtemperature for 7 h. After evaporation, the residue was taken up inchloroform (10 mL) and washed with sat NaHCO₃ (2×5 mL) and brine (5 mL).The organic phase was dried over MgSO₄ and evaporated. The obtainedcrude product (94 mg) was purified by column chromatography on silicagel, eluting with CHCl₃/MeOH 94/6 mixture. In this manner the titlecompound (33 mg, 0.10 mmol, 21%) was obtained.

LCMS/BB_LCMS02(+)/: M+1=332, Rt: 1.86 min.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.47 (br. s., 1H), 10.18 (s, 1H), 7.51(s, 1H), 6.85 (s, 1H), 4.59 (s, 2H), 3.67 (t, J=6.0 Hz, 2H), 3.49 (s,2H), 2.87 (br. s., 10H), 2.71 (s, 3H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 4-1  1-2

BB_LCMS02(+) 332 1.860  97 98 4-2* 1-2

BB_LCMS01(+) 318 1.912 100 98 *isolated from EtOAc with HCl/EtOAc

Example 5 6-Methoxy-1,2,3,4-tetrahydro-isoquinoline-5- and7-carbaldehydes

Step A 5-Formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester and7-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (HI-227d and HI-227i)

To dichloromethane (80 mL) at 0° C., titanium tetrachloride (8.8 mL,15.2 g, 80 mmol) and then dichloromethyl methyl ether (7.2 mL, 9.2 g, 80mmol) were added dropwise followed by the addition of6-methoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride (4.0 g, 20 mmol)in small portions and the mixture was stirred at 0° C. for 3 h. Thereaction was quenched by slow addition of 2 N HCl (50 mL) and the layerswere separated. The organic layer was extracted with 1 N HCl (2×10 mL)and the combined acidic aqueous layers were washed with dichloromethane(1×20 mL). Dichloromethane (100 mL) was added to the aqueous layers andthe pH of the two-phase mixture was adjusted to 10 with 10 N NaOH (70mL) under ice cooling. After addition of di-tert-butyl dicarbonate (4.8g, 22 mmol) the mixture was stirred overnight. The reaction was dilutedwith dichloromethane (120 mL) and water (200 mL), the aqueous layer wasseparated and extracted with dichloromethane (2×100 mL). The combinedorganic layers were washed with water (3×150 mL), dried over MgSO₄ andconcentrated. The residual oil was chromatographed on silica (200 g),eluting first with a 8:1 mixture of n-hexane and ethyl acetate, followedby a 4:1 mixture and finally with a 2:1 mixture of the same solvents. Bycombining the appropriate fractions, concentration and trituration ofthe residues with n-hexane first5-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (1.72 g, 5.9 mmol, 29.5%) and then7-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (2.88 g, 9.9 mmol, 49.5%) were obtained as colorlesssolids.

5a-1: LCMS/BB_LCMS01(+)/: M+1=236, Rt: 3.955 min,

5a-2: LCMS/BB_LCMS01(+)/:M+1=236, Rt: 3.811 min,

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS LCMS Rt purity EXAMPLE Made From Structure method LCMS Ion(min) (%) —

BB_LCMS01(+) 236 3.955 100   n/a —

BB_LCMS01(+) 236 3.811 99.5 n/a —

BB_LCMS01(+) 236 3.855 and 3.926 68.2 and 28.8 n/a *Inseparable mixture

Step B 6-Hydroxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehydehydrochloride

To 5-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (1.41 g, 4.84 mmol) in ethyl acetate (10 mL), a 3.3 Msolution of anhydrous HCl in ethyl acetate was added and the mixture wasstirred at room temperature for 2 h. The precipitated product wascollected, washed with ethyl acetate and dried in air. In this mannerthe title compound (1.03 g, 4.52 mmol, 93.4%) was obtained as a whitepowder.

LCMS/BB_LCMS01(+)/: M+1=192, Rt: 0.654 min,

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 5-1 5a-1

BB_LCMS01(+) 192 0.654 100 n/a 5-2 5a-2

BB_LCMS01(+) 192 0.562 96.4 n/a 5-3 5a-3

BB_LCMS01(+) 192 0.542 98.9 n/a 5-4 5a-3

BB_LCMS01(+) 192 0.745 87.7 n/a

Example 66-Methoxy-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

To a stirred suspension of6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde hydrochloride(91 mg, 0.4 mmol) and nicotinoyl chloride hydrochloride (89 mg, 0.5mmol) in 1,2-dichloroethane (6 mL) diisopropylethylamine (261 μL, 194mg, 1.5 mmol) was added and the mixture was stirred at room temperaturefor 3 h. After dilution with 1,2-dichloroethane (30 mL) the mixture waswashed sequentially with water (5 mL), 1 N aqueous NaOH (5 mL) and againwith water (3×5 mL). After drying over MgSO₄ and concentration, thetitle compound (110 mg, 0.38 mmol, 95%) was obtained as a beige solid.

LCMS/BB_LCMS01(+)/: M+1=297, Rt: 2.792 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 6-1 5-1

BB_LCMS01(+) 297 2.792 98.1 n/a 6-2 5-1

BB_LCMS01(+) 332 3.732 100 n/a 6-3 5-2

BB_LCMS01(+) 332 3.651 97.4 n/a 6-4 5-3

BB_LCMS01(+) 297 2.738 93 n/a 6-5 5-3

BB_LCMS01(+) 332 3.667 98.5 n/a 6-6 5-4

BB_LCMS01(+) 297 2.807 98.2 n/a

Example 76-Methoxy-2-[3-(4-methyl-piperazin-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

To a stirred mixture of6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde hydrochloride(153 mg, 0.67 mmol) and triethylamine (447 μL, 324 mg, 3.2 mmol) inanhydrous tetrahydrofuran (8 mL) 3-(4-methyl-piperazin-1-yl)-propionicacid (172 mg, 1.0 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimidehydrochloride (192 mg, 1.0 mmol) and 1-hydroxy-benzotriazole (135 mg,1.0 mmol) were added in the above order and the mixture was stirred atroom temperature for 3 h. After dilution with ethyl acetate (20 mL) themixture was washed with 1 N aqueous NaOH (3×5 mL) and water (3×5 mL) andthen the product was extracted into 1 N HCl (3×5 mL). The aqueous acidiclayer was rendered alkaline (pH=10) with 10% aqueous NaOH and extractedwith chloroform (3×10 mL). The combined chloroform layers were washedwith water (3×5 mL), dried over MgSO₄ and concentrated. In this mannerthe title compound (206 mg, 0.60 mmol, 89.6%) was obtained as a yellowoil.

LCMS/BB_LCMS01(+)/: M+1=346, Rt: 2.085 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 7-1 5-1

BB_LCMS01(+) 346 2.085 96.4 n/a 7-2 5-1

BB_LCMS01(+) 332 2.293 97 n/a 7-3 5-3

BB_LCMS01(+) 332 2.165 98.6 n/a 7-4 5-3

BB_LCMS01(+) 346 1.996 96.7 n/a

Example 8 5-Formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid (2-morpholin-4-yl-ethyl)-amide

Step A2-(Imidazole-1-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

To a solution of freshly dried di-imidazol-1-yl-methanone (276 mg, 1.7mmol) in anhydrous tetrahydrofuran (20 mL) the solution of6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (325 mg, 1.7mmol) in anhydrous tetrahydrofuran (10 mL) was added and the mixture wasstirred at 80° C. oil bath for 14 h. The solution was concentrated andthe residue was dissolved in dichloromethane, washed with water (2×10mL), dried over MgSO₄ and concentrated. In this manner the titlecompound (426 mg, 1.50 mmol, 88.2%) was obtained as a brownish yellowfoam.

LCMS/BB_LCMS01(+)/: M+1=286, Rt: 2.524 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 8a-1 5-1

BB_LCMS01(+) 286 2.524 93.5 n/a 8a-2 5-2

BB_LCMS01(+) 286 2.390 92.9 n/a

Step B3-(5-Formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-iumiodide

A mixture of2-(imidazole-1-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde(426 mg, 1.50 mmol) and methyl iodide (475 μL, 1.05 g, 7.6 mmol) inanhydrous acetonitrile (10 mL) was stirred at room temperature for 24 h.After evaporation of the solvent the title compound (640 mg, 1.50 mmol,100%) was obtained as a brownish foam.

LCMS/BB_LCMS01(+)/: M+1=300, Rt: 2.251 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 8b-1 8a-1

BB_LCMS01(+) 300 2.251 92.2 n/a 8b-2 8a-2

BB_LCMS01(+) 300 2.103 82.4 n/a

Step C 5-Formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid(2-morpholin-4-yl-ethyl)-amide

A mixture of3-(5-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-iumiodide (321 mg, 0.75 mmol), 2-(morpholin-4-yl)-ethylamine (99.5 μL, 99.5mg, 0.75 mmol) and triethylamine (106 μL, 76 mg, 0.75 mmol) in anhydrousdichloromethane (10 mL) was stirred at room temperature for 24 h. Afterdilution with dichloromethane (10 mL), the solution was washed withbrine (2×5 mL), dried over MgSO₄ and concentrated. The residue waspurified by column chromatography over silica, eluting with a 9:1mixture of chloroform and methanol. In this manner the title compound(154 mg, 0.44 mmol, 58.7%) was obtained.

LCMS/BB_LCMS01(+)/: M+1=348, Rt: 2.343 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 8-1 8b-1

BB_LCMS01(+) 348 2.343 98.7 n/a 8-2 8b-1

BB_LCMS01(+) 318 2.403 100 n/a 8-3 8b-2

BB_LCMS01(+) 348 2.336 96.1 n/a 8-4 8b-2

BB_LCMS01(+) 318 2.258 96 n/a

Example 92-Benzyl-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde

To a mixture of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehydehydrochloride (114 mg, 0.5 mmol) and freshly dried K₂CO₃ (173 mg, 1.25mmol) in anhydrous dimethylformamide (5 mL), benzyl chloride (69 μL, 76mg, 0.6 mmol) was added and the mixture was stirred at room temperaturefor 24 h. The mixture was poured into water (25 mL) and extracted withdiethyl ether (3×10 mL). The combined organic layers were washed withbrine (3×5 mL), dried over MgSO₄ and concentrated. The title compound(112 mg, 0.40 mmol, 80%) was obtained as a yellow oil.

LCMS/BB_LCMS01(+)/: M+1=282, Rt: 2.415 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 9-1 5-2

BB_LCMS01(+) 282 2.430 95 n/a 9-2 5-1

BB_LCMS01(+) 282 2.538 67.3 n/a 9-3 5-3

BB_LCMS01(+) 282 2.436 82.9 n/a

Example 106-Methoxy-2-[4-methyl-5-(morpholine-4-carbonyl)-thiazol-2-yl]-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

Step A (2-Chloro-4-methyl-thiazol-5-yl)-morpholin-4-yl-methanone

A mixture of 2-bromo-4-methyl-thiazole-5-carboxylic acid (1.11 g, 5.0mmol) and thionyl chloride (11 mL, 18.2 g, 0.153 mol) was heated underreflux for 30 min. After cooling, the volatiles were evaporated,followed by addition and evaporation of three 10 mL portions of toluene.A sample of the residue was treated with methanol and the obtainedmethyl ester was shown to be the 2-chlorothiazole compound[LCMS/BB_LCMS01(+)/: M+1=192, Rt: 3.424 min] indicating that the product(0.91 g, 4.7 mmol, 95%) was 2-chloro-4-methyl-thiazole-5-carbonylchloride.

To a solution of the above acid chloride (200 mg, 1.02 mmol) indichloromethane (5 mL) at 0° C., a mixture of morpholine (88 μL, 89 mg,1.02 mmol) and diisopropylethylamine (148 μL, 124 mg, 1.03 mmol) indichloromethane (3 mL) was added dropwise and the reaction mixture wasstirred at room temperature for 1 h. After dilution with dichloromethane(20 mL) the solution was washed with water (2×5 mL), dried over MgSO₄and evaporated to yield the title compound (208 mg, 0.84 mmol, yield:82% calculated from the starting acid chloride) as a yellow oil.

LCMS/BB_LCMS01(+)/: M+1=247, Rt: 2.534 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 10a-1 —

BB_LCMS01(+) 247 2.534 1011 n/a 10a-2 —

BB_LCMS01(+) 290 0.777 100 n/a

Step A′ 2-Bromo-4-methyl-thiazole-5-carboxylic acid(1-methyl-piperidin-4-yl)-amide

To a stirred mixture of 1-methyl-4-aminopiperidine (125 μL, 114 mg, 1mmol) and triethylamine (570 μL, 414 mg, 4.1 mmol) in anhydroustetrahydrofuran (10 mL), 2-bromo-4-methyl-thiazole-5-carboxylic acid(266 mg, 1.2 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimidehydrochloride (232 mg, 1.2 mmol) and 1-hydroxy-benzotriazole (164 mg,1.2 mmol) were sequentially and the mixture was stirred at roomtemperature for 22 h. After dilution with dichloromethane (20 mL), themixture was washed with water (3×10 mL), dried over MgSO₄ andconcentrated. In this manner the title compound (277 mg, 0.87 mmol, 87%)was obtained as a yellow solid.

LCMS/BB_LCMS01(+)/: M+1=318, Rt: 1.102 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 10a-3 —

BB_LCMS01(+) 318 1.102 96.8 n/a 10a-4 —

BB_LCMS01(+) 348 3.620 93.8 n/a 10a-5 —

BB_LCMS01(+) 304 0.555 99.1 n/a 10a-6 —

BB_LCMS01(+) 290 0.492 100 n/a

Step B6-Methoxy-2-[4-methyl-5-(morpholine-4-carbonyl)-thiazol-2-yl]-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

A mixture of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehydehydrochloride (82 mg, 0.36 mmol), anhydrous dimethylformamide (5 mL),(2-chloro-4-methyl-thiazol-5-yl)-morpholin-4-yl-methanone (89 mg, 0.36mmol) and freshly dried potassium carbonate (149 mg, 1.08 mmol) wasstirred under argon at 120° C. for 3.5 h and then at 150° C. for 1 h.Water (20 mL) was added and the separated solid product was filteredoff. The filtrate was extracted with diethyl ether (5×10 mL) and thecombined extracts were washed with water (2×10 mL), dried andconcentrated. The residue and the above solid product were combined andtriturated repeatedly with diisopropyl ether. In this manner the titlecompound (37 mg, 0.092 mmol, 26%) was obtained as a beige powder.

LCMS/BB_LCMS01(+)/: M+1=402, Rt: 3.129 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 10-1 10a-1

BB_LCMS01(+) 402 3.129 88.9 n/a 10-2 10a-2

BB_LCMS01(+) 445 2.655 96.1 n/a 10-3 10a-3

BB_LCMS01(+) 429 2.624 91.3 n/a 10-4 10a-4

BB_LCMS01(+) 515 3.849 90.7 n/a 10-5 10a-5

n/a 10-6 10a-6

n/a 10-7 10a-5

BB_LCMS01(+) 415 2.470 96 n/a 10-8 10a-6

n/a

Example 114-(7-Formyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-benzamide

Step A4-(7-Formyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-benzonitrile

A mixture of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehydehydrochloride (1.0 g, 4.39 mmol), 1-fluoro-4-methyl-benzene (2.42 g,20.0 mmol) and freshly dried K₂CO₃ (3.0 g, 21.7 mmol) in anhydrousdimethylformamide (11 mL) was stirred under nitrogen at 130° C. for 6 h.The mixture was poured into water (50 mL) and extracted with ethylacetate (3×50 mL). The organic extracts were dried over MgSO₄ andevaporated. The residue was purified by column chromatography oversilica by eluting with a 2:1 mixture of n-hexane and ethyl acetate. Inthis manner the title compound (0.45 g, 1.54 mmol, 35.1%) was obtained.

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (mm) (%) (%) 11a —

BB_LCMS01(+) 293 3.828 100 n/a

Step B 4-(5-Formyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-benzamide

A mixture of4-(7-formyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-benzonitrile (200mg, 0.68 mmol) and 96% (w/w) sulfuric acid (3 mL) was stirred at roomtemperature overnight. The next day poured onto ice-water (10 mL), thepH was adjusted with K₂CO₃ to 9 and the mixture was extracted with ethylacetate. The residue was purified by column chromatography over silica,eluting with a 95:5 mixture of chloroform and methanol. In this mannerthe title compound (85 mg, 0.27 mmol, 39.7%) was obtained as a solid.

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 11-1 11a

BB_LCMS01(+) 311 3.121 100 n/a

Example 126-Methoxy-2-[2-(4-methyl-piperazin-1-yl)-thiazole-5-carbonyl]-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

Step A2-(2-Bromo-thiazole-5-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

To a mixture of dry tetrahydrofuran (20 mL)6-Methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde hydrochloride(683 mg, 3.00 mmol), and triethylamine (2.1 mL, 1.52 g, 15 mmol),2-bromothiazole-5-carboxylic acid (655 mg, 3.15 mmol),1-hydroxybenzotriazole (446 mg, 3.30 mmol) and1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (634 mg, 3.30mmol) were added sequentially. The mixture was stirred at roomtemperature for 2 h and the resulted yellow suspension was evaporatedand partitioned between chloroform (30 mL) and 0.1N HCl (15 mL). Theorganic layer was separated and washed with saturated sodium bicarbonate(15 mL) and brine (15 mL). The organic phase was dried, evaporated andpurified by column chromatography (Kieselgel 60), with chloroform as theeluent. The title compound (600 mg, 1.57 mmol, 53%) was isolated as asolid.

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 12a —

BB _LCMS01(+) 382 3.470 100 n/a

Step B6-Methoxy-2-[2-(4-methyl-piperazin-1-yl)-thiazole-5-carbonyl]-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde

To a solution of2-(2-Bromo-thiazole-5-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde(229 mg, 0.60 mg) in abs. N,N-dimethylformamide (4 mL), N-methylpiperazine (133 μL, 120 mg, 1.20 mmol) and dry potassium carbonate (248mg, 1.80 mmol) was added. The resultant mixture was stirred undernitrogen at 100° C. for 2 h in a closed vial. The reaction was cooled,water (10 mL) was added, and the resultant solution was extracted withethyl acetate (3×15 mL) The combined organic layers were dried (MgSO₄)and evaporated to afford title compound (92 mg, 0.23 mmol, 38%) as apale yellow crystalline solid.

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 12-1 12a

BB_LCMS01(+) 401 2.550 93 n/a

Example 137-Hydroxy-3-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-2-oxo-2H-chromene-8-carbaldehyde

A mixture of7-hydroxy-3-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-chromen-2-one(156 mg, 0.40 mmol) and hexamethylenetetramine (224 mg, 1.6 mmol) intrifluoroacetic acid (4 mL) was stirred in a closed vial under argon at110° C. for 40 min. After cooling water (15 mL) was added and themixture was extracted with dichloromethane (3×5 mL). The combinedorganic extracts were washed with water (3×5 mL), dried over MgSO₄ andconcentrated. The obtained crude product (83 mg) was purified by columnchromatography over silica, eluting with a 9:1 mixture of chloroform andmethanol. In this manner the title compound (30.5 mg, 0.074 mmol, 18.5%)was obtained as a yellow solid.

LCMS/BB_LCMS01(+)/: M+1=414, Rt: 3.085 min.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.41 (s, 1H), 8.86 (s, 1H), 7.97 (d,J=9.0 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 3.59 (br. s., 4H), 2.55-2.64 (m,4H), 2.41 (s, 3H), 2.38 (s, 3H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 13-1 20-1

BB_LCMS01(+) 414 3.085 100 98 13-2 6093- 68-1

BB_LCMS01(−) 189 2.621 100 98 13-3 23251- 28-7

BB_LCMS01(−) 231 3.505 98 95 13-4 20052- 60-2

BB_LCMS01(+) 235 3.709 96 97 13-5 56437- 16-2

BB_LCMS01(−) 233 2.496 95 98 13-6 Indofine 19-244

BB_LCMS01(−) 345 4.068 100 98 13-7 Princeton PBMR- 019293

BB_LCMS01(+) 355 3.495 100 98 13-8 Princeton PBMR- 015251

BB_LCMS01(+) 311 3.467 94 95 13-9 Princeton PBMR- 001612

BB_LCMS01(+) 316 4.081 97 98 13-10 61034- 11-5

BB_LCMS01(+) 333 3.785 100 98 13-11 19492- 02-5

BB_LCMS01(−) 237 3.453 98 98 13-12 219965- 92-1

BB_LCMS01(−) 221 3.177 93 98 13-13 5852- 03-9

BB_LCMS01(−) 261 3.224 88 90 13-14 90-33-5

BB_LCMS01(+) 205 3.278 100 98 13-15 6100- 60-3

BB_LCMS07(+) 321 1.401 98 98 13-16 55977- 10-1

BB_LCMS01(−) 281 3.453 95 n/a 13-17 19a-1

BB_LCMS01(−) 344 3.844 90 95 13-18 19a-2

BB_LCMS01(−) 358 3.948 97 96 13-19 20-2

BB_LCMS01(+) 444 3.124 100 98 13-20 20-3

BB_LCMS01(+) 428 3.033 100 94 13-21 20-5

BB_LCMS07(+) 400 1.276 99 98 13-22 21-1

BB_LCMS01(+) 401 3.359 96 95 13-23 22-1

BB_LCMS01(−) 311 3.290 100 98 13-24 22-2

BB_LCMS01(−) 299 3.419 99 98 13-25 22-3

BB_LCMS01(−) 315 3.229 79 n/a

Example 14[4-(6-Hydroxy-benzothiazol-2-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone

3-Bromo-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (142 mg,0.50 mmol), 4-(4-morpholine-4-carbonyl)phenylboronic acid pinacol ester(175 mg, 0.55 mmol), potassium phosphate (424 mg, 2.00 mmol) andtetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol) were dissolvedin a degassed mixture of 4.5 mL 2-ethoxyethanol and 0.5 mL water. Themixture was stirred at 115° C. under argon for 2 h. The reaction mixturewas allowed to reach room temperature, then activated-carbon (40 mg) wasadded and was stirred for 20 min. The solid was filtered off, washedwith ethanol and the combined filtrates were evaporated. The residue wassuspended in saturated sodium bicarbonate (20 mL) and extracted withdichloromethane (3×20 mL). The combined organic layers were dried(Na₂SO₄) and evaporated. The solid residue was purified by columnchromatography (Kieselgel 60) with chloroform-methanol 98:2 as theeluent. The crude product was triturated with Et₂O, filtered off and airdried, affording the title compound (31 mg, 0.08 mmol, 16%) as a whitepowder.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 14-1 55977- 10-1

BB_LCMS01(+) 394 3.175 100 98 14-2 55977- 10-1

BB_LCMS01(+) 407 2.596 99 98 14-3 55977- 10-1

BB_LCMS01(+) 437 2.714 100 98 14-4 55977- 10-1

BB_LCMS01(+) 394 3.199 99 98 14-5 55977- 10-1

BB_LCMS01(+) 380 2.574 97 98 14-6 55977- 10-1

BB_LCMS01(+) 352 3.233 96 98 14-7 55977- 10-1

BB_LCMS01(+) 378 3.416 99 98 14-8 55977- 10-1

BB_LCMS01(+) 406 3.815 94 98 14-9 55977- 10-1

BB_LCMS01(+) 352 3.292 98 98 14-10 55977- 10-1

BB_LCMS01(+) 378 3.439 95 98 14-11 13-23

BB_LCMS01(+) 409 2.929 100 95 14-12 13-23

BB_LCMS01(+) 424 3.196 96 95 14-13 13-23

BB_LCMS01(+) 437 3.020 100 98 14-14 13-24

BB_LCMS01(+) 397 3.017 92 95 14-15 13-25

BB_LCMS01(+) 428 3.550 94 98

Example 157-hydroxy-4-methyl-3-(3-morpholin-4-yl-3-oxo-propyl)-2-oxo-2H-chromene-8-carbaldehyde

Step A 3-(8-Formyl-7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-propionicacid

A mixture of 3-(7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-propionic acidethyl ester (100 mg, 0.36 mmol) and hexamethylenetetramine (203 mg, 1.44mmol) in trifluoroacetic acid (3.6 mL) was stirred in a closed vialunder argon at 110° C. for 2 h. The reaction was poured onto crushed ice(15 mL), warmed to room temperature, and the solid precipitate wasfiltered off. This mixture of formylated ester and correspondingcarboxylic acid was dissolved in dioxane-1N NaOH (1:1) and was stirredat room temperature. After 2 h, 15 mL of dichloromethane was added. Theaqueous layer was separated and acidified by portionwise addition of 1NHCl. The precipitate was collected, washed with water, and dried toafford title compound (15 mg, 0.043 mmol, 13%) as a light brown powder.

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 15a-1 5969- 19-7

BB_LCMS01(+) 277 3.268 90 n/a 15a-2 6100- 60-3

BB_LCMS07(+) 307 1.386 79 n/a

Step B7-Hydroxy-4-methyl-3-(3-morpholin-4-yl-3-oxo-propyl)-2-oxo-2H-chromene-8-carbaldehyde

To a mixture of dry tetrahydrofuran (8.5 mL) and N,N-dimethylformamide(2 mL), morpholine (93 μL, 94 mg, 1.08 mmol), triethylamine (340 μl, 247mg, 2.45 mmol)3-(8-formyl-7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-propionic acid(148 mg, 0.49 mmol), 1-hydroxybenzotriazole (146 mg, 1.08 mmol) and1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (205 mg, 1.08mmol) were added in order. The mixture was stirred at room temperatureovernight, then 5 mL of 2N HCl was added and the stirring was continuedfor 2 h. The resultant solution was extracted with dichloromethane (2×10mL), the combined organic layers were washed with saturated sodiumbicarbonate (10 mL) and brine (10 mL), the organic phase was dried(Na₂SO₄) and evaporated. The title compound (399 mg, 1.070 mmol, 57%)was isolated by column chromatography (Kieselgel 60), withchloroform-methanol 20:1 as eluent, as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.74 (br. s., 1H), 10.45 (s, 1H), 7.98(d, J=9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 3.49-3.60 (m, 4H), 3.39-3.45(m, 4H), 2.75-2.81 (m, 2H), 2.47-2.53 (m, 2H), 2.41 (s, 3H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 15-1 15a-1

BB_LCMS01(+) 346 2.286 99 98 15-2 15a-1

BB_LCMS01(+) 359 2.945 100 98 15-3 15a-1

BB_LCMS01(+) 389 2.928 98 97 15-4 15a-2

BB_LCMS07(+) 376 1.199 100 98 15-5 5852- 10-8

BB_LCMS07(+) 332 1.404 100 98 15-6 5852- 10-8

BB_LCMS07(+) 345 1.307 99 98

Example 167-Hydroxy-4-methyl-3-[3-(4-methyl-piperazin-1-yl)-3-oxo-propenyl]-2-oxo-2H-chromene-8-carbaldehyde

3-Bromo-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (142 mg,0.50 mmol), 1-(4-methyl-piperazin-1-yl)-propenone (93 mg, 0.60 mmol),palladium acetate (4 mg, 15 μmol), tri-o-tolyl-phosphane (9 mg, 30 μmol)and silver acetate (167 mg, 1.0 mmol) were dissolved in abs.N,N-dimethylformamide (4 mL). The mixture was irradiated in a microwavereactor for 1 h at 120° C. under inert atmosphere. The reaction mixturewas poured into water (10 mL) and extracted with chloroform (3×15 mL).The combined organic layers were dried (Na₂SO₄) and evaporated. Thetitle compound (15 mg, 0.042 mmol, 8%) was isolated by columnchromatography (Kieselgel 60), with chloroform as eluent, as a yellowpowder.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.43 (s, 1H), 8.05 (d, J=9.0 Hz, 1H),7.59 (d, J=15.1 Hz, 1H), 7.50 (d, J=15.1 Hz, 1H), 6.92 (d, J=9.0 Hz,1H), 3.56-3.66 (m, 4H), 2.55 (s, 3H), 2.38 (br. s., 4H), 2.27 (s, 3H).

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 16-1 55977- 10-1

BB_LCMS01(+) 357 3.011 99 94

Example 17 7-Hydroxy-4-methyl-2-oxo-2H-chromene-3-carbothioic acid amide

To a solution of 7-Hydroxy-4-methyl-2-oxo-2H-chromene-3-carbonitrile(7.50 g, 37.31 mmol) in N,N-dimethylformamide (150 mL), ammonium sulfide(40-48 wt % solution in water; 38 mL, 560 mmol) was added, and theresulted mixture was stirred at room temperature for a week. Anadditional portion of ammonium sulfide (38 mL) was added on every secondday. The solution was evaporated and the solid residue was trituratedwith water, filtered and dried. The obtained crude product was purifiedby column chromatography (Kieselgel 60), with chloroform-methanol (1:1)as eluent. The title compound (3.20 g, 13.6 mmol, 36%) was isolated as ayellow powder.

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 17-1 2829- 46-1

BB_LCMS01(+) 236 2.554 99 n/a

Example 187-methoxy-3-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-chromen-2-one

Step A2-(7-Hydroxy-2-oxo-2H-chromen-3-yl)-4-methyl-thiazole-5-carboxylic acidtert-butyl ester

To a suspension of 7-hydroxy-2-oxo-2H-chromene-3-carbothioic acid amide(221 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) stirred at0° C., sodium hydride (60% in oil, 44 mg, 1.1 mmol) was addedportionwise. During addition a clear solution was formed with moderateeffervescence. After 10 min, a solution of 2-bromo-3-oxo-butyric acidtert-butyl ester (474 mg, 2.0 mmol) in anhydrous N,N-dimethylformamide(2 mL) was added dropwise and the mixture was stirred at roomtemperature for 16 h. The reaction was poured into water (20 mL) andextracted with chloroform (3×10 mL). The combined organic extracts werewashed with water (3×5 mL), dried over MgSO₄ and concentrated. Theresidue was triturated with diethyl ether, the solid product wascollected and washed with diethyl ether. The title compound (224 mg,0.623 mmol, 62.3%) was obtained as a yellow solid.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 18a-1 69015- 66-3

BB_LCMS07(+) 360 3.928 97.1 n/a 18a-2 17-1

BB_LCMS07(+) 374 3.913 96.3 n/a

Step B2-(7-Hydroxy-2-oxo-2H-chromen-3-yl)-4-methyl-thiazole-5-carboxylic acid

To a suspension of2-(7-hydroxy-2-oxo-2H-chromen-3-yl)-4-methyl-thiazole-5-carboxylic acidtert-butyl ester (387 mg, 1.08 mmol) and anisole (117 μL, 117 mg, 1.08mmol) in anhydrous dichloromethane (5 mL) was added trifluoroacetic acid(5 mL) and the obtained solution was stirred at room temperature for 6h. Diethyl ether (30 mL) was added, the precipitate was collected,washed with diethyl ether and dried in air. In this manner the titlecompound (285 mg, 0.94 mmol, 87%) was obtained as a light brown solid.

LCMS/BB_LCMS01(+)/: M+1=304, Rt: 3.297 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made Rt purity purity Ex From Structure LCMS method LCMSIon (min) (%) (%) 18-1 18a-1

BB_LCMS07(+) BB_LCMS07(+) 304 3.297 99.3 18-2 18a-2

BB_LCMS07(+) BB_LCMS07(+) 318 3.293 99.7

Example 19

Step A2-(7-Hydroxy-2-oxo-2H-chromen-3-yl)-4-methyl-thiazole-5-carboxylic acidethyl ester

To a solution of 7-hydroxy-2-oxo-2H-chromene-3-carbothioic acid amide(66 mg, 0.3 mmol) in anhydrous N,N-dimethylformamide (5 mL), freshlydried K₂CO₃ (263 mg, 1.9 mmol) was added followed by2-chloro-3-oxo-butyric acid ethyl ester (79 μL, 94 mg, 0.54 mmol) andthe mixture was stirred at room temperature for 19 h. The mixture waspoured into water (25 mL) and extracted first with chloroform (3×10 mL)and, after saturation with NaCl, with tetrahydrofuran (3×10 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated. Theresidue was dissolved in chloroform (8 mL), pyridiniump-toluenesulfonate (7.5 mg, 0.03 mmol) was added and the mixture wasstirred at 60° C. for 4.5 h. After cooling, the solution was washed withbrine (3×5 mL), dried over MgSO₄ and concentrated. The residue waspurified by column chromatography on silica, eluting with a 9:1:0.1mixture of chloroform, methanol and cc. NH₄OH. The title compound (14.5mg, 0.044 mmol, 14.7%) was obtained as a yellow solid.

LCMS/BB_LCMS01(+)/: M+1=332, Rt: 3.748 min.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 19a-1 69015- 66-3

BB_LCMS07(+) 318 3.643 98.9 n/a 19a-2 69015- 66-3

BB_LCMS07(+) 332 3.748 90.4 n/a

Step B 2-(7-Hydroxy-2-oxo-2H-chromen-3-yl)-thiazole-5-carboxylic acid)

A suspension of2-(7-hydroxy-2-oxo-2H-chromen-3-yl)-thiazole-5-carboxylic acid ethylester (50 mg, 0.16 mmol) in 70% (w/w) sulfuric acid (3 mL) was stirredat 100° C. for 1 h. During heating the solids dissolved and a solidprecipitated after 1 h. The precipitate was collected, washed with waterand dried in air. In this manner the title compound (30.5 mg, 0.10 mmol,62.5%) was obtained as a pale brown solid.

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 19-1 19a-1

BB_LCMS07(+) 290 3.181 98 n/a

Example 207-Hydroxy-4-methyl-3-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-chromen-2-one

To dry tetrahydrofuran (12 mL) at 0° C., 1-methylpiperazine (61 μL, 55mg, 0.55 mmol), triethylamine (210 μL, 152 mg, 1.5 mmol),2-(7-hydroxy-2-oxo-2H-chromen-3-yl)-4-methyl-thiazole-5-carboxylic acid(156 mg, 0.49 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimidehydrochloride (105 mg, 0.55 mmol) and 1-hydroxybenzotriazole monohydrate(84 mg, 0.55 mmol) were added sequentially, and the mixture was stirredat room temperature for 16 h. After addition of water (30 mL) the pH wasadjusted to 8 by addition of a 5% aqueous solution of NaHCO₃ and themixture was extracted with tetrahydrofuran (3×15 mL). After drying(MgSO₄) and evaporation, the residue was purified by columnchromatography over silica (Kieselgel 60) using chloroform-methanol 9:1as eluent. The title compound (156 mg, 0.41 mmol, 81%) was obtained as ayellow solid.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 20-1 18-1

BB_LCMS07(+) 386 2.955 100 n/a 20-2 18-1

BB_LCMS07(+) 416 2.966 100 n/a 20-3 18-2

BB_LCMS07(+) 400 2.949 100 n/a 20-4 18-2

BB_LCMS07(+) 430 3.001 100 n/a 20-5 19-1

BB_LCMS07(+) 372 1.215 95.8 n/a

Example 217-Hydroxy-3-[4-methyl-5-(morpholine-4-carbonyl)-thiazol-2-yl]-chromen-2-one

To a solution of 1-morpholin-4-yl-butane-1,3-dione (0.53 g, 3.1 mmol) in1,2-dichloroethane (30 mL) stirred at 0° C., N-bromosuccinimide (0.55mg, 3.1 mmol) was added in small portions and the mixture was stirredfor 1 h. The solution was washed with brine (3×5 mL), dried over MgSO₄and concentrated below 30° C. 2-Bromo-1-morpholin-4-yl-butane-1,3-dione0.76 g, 3.04 mmol, 98.1%, LCMS/BB_LCMS01(+)/: M+1=250, 252, Rt: 1.831min] was obtained as a yellowish oil.

To a stirred suspension of 7-hydroxy-2-oxo-2H-chromene-3-carbothioicacid amide (354 mg, 1.6 mmol) in anhydrous N,N-dimethylformamide (7 mL),1,8-diazabicyclo-[5.4.0]undec-7-ene (480 μL, 490 mg, 3.2 mmol) was addedfollowed by a solution of 2-bromo-1-morpholin-4-yl-butane-1,3-dione (750mg, 3.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) and the mixturewas stirred at room temperature for 15 h. The reaction mixture waspoured into water (100 mL) and extracted first with chloroform (3×30 mL)then after saturation with NaCl, with tetrahydrofuran (3×50 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated. Theresidue was dissolved in chloroform (16 mL), pyridiniump-toluenesulfonate (40.2 mg, 0.16 mmol) was added and the mixture wasstirred at 60° C. for 4.5 h. The reaction mixture was washed with amixture of brine (10 mL) and 5% NaHCO₃ solution (5 mL) and then withbrine (2×15 mL), dried over MgSO₄ and concentrated. The residue waspurified by column chromatography on silica, eluting with a 9:1:0.1mixture of chloroform, methanol and cc. NH₄OH. The title compound (34.6mg, 0.093 mmol, 5.8%) was obtained as a yellow solid.

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 21-1 69015- 66-3

BB_LCMS01(+) 373 3.040 100 n/a

Example 22 3-Bromo-7-hydroxy-6-methoxy-4-methyl-chromen-2-one

A bromine (2.55 g, 15.96 mmol) solution in acetic acid (8 mL) was addeddropwise to a stirred suspension of7-hydroxy-6-methoxy-4-methyl-chromen-2-one (3.20 g, 15.5 mmol) inglacial acetic acid (31 mL) at room temperature. The mixture was stirredfor 10 min, then poured onto crushed ice (400 mL). To the resultantlight yellow suspension, 1 mL of saturated sodium bisulphite solutionwas added and the mixture was allowed to reach room temperature. Theprecipitated solids were filtered off, washed with water, dried andrecrystallized from glacial acetic acid. The obtained white powder (3.39g, 11.88 mmol, 76%) was used without further purification.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity Ex From Structure LCMS methodIon (min) (%) (%) 22-1 3374- 03-6

BB_LCMS01(+) 286 3.316 78 n/a 22-2 219965- 92-1

BB_LCMS01(+) 274 3.390 92 n/a 22-3 19492- 02-5

BB_LCMS01(+) 289 3.589 92 n/a

Example 23

Step A7-hydroxy-4-methyl-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)-2H-chromen-2-one(3)

A mixture of 3-bromo-7-hydroxy-4-methyl-2H-chromen-2-one (1) (7.66 g, 30mmol), 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid hydrochloride(2) (10.24 g, 36 mmol), Na₃PO₄ (22.14 g, 135 mmol), ethoxyethanol (140g) and water (14 g) was purged with Argon for five minutes in a 250 mLpressure vessel. Ligand Sphos (obtained from Aldrich, Cat No. 638072)(739 mg, 1.8 mmol) and Pd(OAc)₂ (202 mg, 0.90 mmol) were added under anArgon atmosphere then the vessel was sealed and heated for 60 min in a150° C. oil bath with strong stirring. This process was repeated once.Upon cooling, the reaction mixtures were filtered through a silica plugusing CH₂Cl₂ and MeOH wash. The unified solutions were evaporated to 100mL slowly diluted with water (100 mL) and crystallized at 0° C. Theproduct was filtered, washed with 50% MeOH (2×30 mL) and dried to afford18.52 g (81%) of the title compound. MS (ESI): 379 (M+H)⁺. ¹H NMR (δ,DMSO (2.5 ppm)): 10.57 (s, br, 1H), 7.69 (d, 1H), 7.44 (d, 2H), 7.36 (d,2H), 6.84 (dd, 1H), 6.76 (d, 1H), 3.65-3.30 (m, 8H), 2.23 (s, 3H), 2.20(s, 3H).

Step B7-hydroxy-4-methyl-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)-2-oxo-2H-chromene-8-carbaldehydehydrochloride (4)

A mixture of7-hydroxy-4-methyl-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)-2H-chromen-2-one(3) (9.11 g, 24.0 mmol) and hexamethylenetetramine (13.46 g, 96.0 mmol)in TFA (283 g) was heated in a pressure flask in a 120° C. oil bath for40 minutes. This process was repeated once. Upon cooling, the unifiedsolutions were evaporated to 182 g weight and, after addition of CH₂Cl₂(500 mL) and water (100 mL) it was cooled to 0° C. The mixture wasneutralized with NaOH (2N, 400 mL) and then close to the end point withNaHCO₃ (10%) with cooling and stirring. The product was extracted withCH₂Cl₂ (5×100 mL), washed with water (backextracted), dried on MgSO₄ andevaporated to afford 23.5 g crude product. The crude product was loadedon 33 g silica and purified by medium pressure chromatography (4×100gcolumns+4×100g reruns) using 2-3% MeOH in CH₂Cl₂ by collecting the frontfractions to afford 7.00 g of free base This product was dissolved inEtOH (130 mL) and HCl (8 mL, 6N) with heating. Upon cooling to 20° C.the salt crystallized. It was filtered and washed with abs EtOH (2×20mL), dried on air then at 50° C. under 5 Hgmm vacuum to afford 6.65 g(34%) of the title compound.

MS (ESI): 407 (M+H)⁺.

¹H NMR (δ, DMSO (2.5 ppm)): 11.93 (s, br, 1H), 10.90 (s, br, 1H), 10.50(s, 1H), 8.04 (d, 1H), 7.55 (d, 2H), 7.43 (d, 2H), 7.04 (d, 1H), 4.4-3.3(m, br, 8H), 2.79 (s, 3H), 2.28 (s, 3H).

Elemental analysis of a previous air dried sample corresponds well to 2crystal water:

Measured Calculated % Air dried^(a) Deep dried^(b) 4 4 + H₂O 4 + 2H₂O C57.66 60.91 62.37 59.94 57.68 H 5.61 5.75 5.23 5.47 5.68 N 5.78 6.116.33 6.08 5.85 Cl 7.47 7.75 8.00 7.69 7.40 Pd <10 ppm <10 ppm ^(a)Airdried: equilibrated at 22° C. ^(b)Deep dried: equilibrated at 50° C.under 1 Hgmm for 24 hours.

Example 24

Step A4-(7-Hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)benzamide(6)

A mixture of 3-bromo-7-hydroxy-4-methyl-2H-chromen-2-one (1) (7.66 g, 30mmol), 4-(2-morpholinoethylcarbamoyl)phenylboronic acid (2) (10.02 g, 36mmol), Na3PO4 (17.21 g, 105 mmol) in a mixture of ethoxyethanol (140 g)and water (14 g) was purged with Argon for five minutes in a 250 mLpressure vessel. Ligand Sphos (738 mg, 1.8 mmol) and Pd(OAc)2 (206 mg,0.90 mmol) were added under an Argon atmosphere then the vessel wassealed and heated for 60 min in a 150° C. oil bath with strong stirring.This process was repeated once. Upon cooling, the reaction mixtures werefiltered through a silica plug using CH₂Cl₂ and MeOH wash. The unifiedsolutions were evaporated to 100 mL slowly diluted with water (100 mL)and crystallized at 0° C. The product was filtered, washed with 50% MeOH(2×50 mL) and dried to afford 22.33 g (91%) of the title compound. MS(ESI): 409 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 10.57 (s, br, 1H), 8.46(t, 1H), 7.88 (d, 2H), 7.69 (d, 1H), 7.39 (d, 2H), 6.84 (dd, 1H), 6.76(d, 1H), 3.57 (m, 4H), 3.40 and 2.48 (2q, 2×2H), 2.43 (m, 4H), 2.22 (s,3H).

Step B4-(8-Formyl-7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)benzamide(4)

A mixture of4-(7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)benzamide(3) (8.17 g, 20.0 mmol) and hexamethylenetetramine (11.22 g, 80.0 mmol)in TFA (200 mL) was heated in a pressure flask in a 115° C. oil bath for40 minutes. This process was repeated once. Upon cooling, the unifiedsolutions were evaporated to 158 g weight and, after addition of CH₂Cl₂(500 mL) and water (100 mL) it was cooled to 0° C. The mixture wasneutralized with NaOH (2N, 350 mL) and then close to the end point withNaHCO₃ (10%) with cooling and stirring. The product was extracted withCH₂Cl₂ (5×100 mL), washed with water (backextracted), dried on MgSO₄ andevaporated to afford 17.2 g crude product. The crude product was loadedon 40 g silica and purified by medium pressure chromatography (4×100gcolumns) using 1-3% MeOH in CH₂Cl₂ by collecting the front fractions toafford 6.2 g (31%) of the title compound. This product can be turnedinto its HCl salt by dissolving it in EtOH (100 mL) and adding 6N HCl(10 mL). The salt was filtered and washed with 70% EtOH (2×20 mL), driedon air then at 50° C. under 5 Hgmm vacuum to afford 6.0 g HCl salt ofthe title compound.

MS (ESI): 437 (M+H)⁺.

¹H NMR (δ, DMSO (2.5 ppm)): 10.50 (s, 1H), 8.48 (t, 1H), 8.02 (d, 1H),7.89 (d, 2H), 7.42 (d, 2H), 7.00 (d, 1H), 3.58 (t, 4H), 3.41 and 2.50(2q, 2×2H), 2.48 (m, 4H), 2.25 (s, 3H). HCl-salt: 11.93 (s, br, 1H),10.62 (s, br, 1H), 10.50 (s, 1H), 8.96 (t, 1H), 8.04 (d, 1H), 8.00 (d,2H), 7.45 (d, 2H), 7.04 (d, 1H), 3.98, 3.79, 3.71, 3.55, 3.34, 3.14 (6m,6×2H), 2.26 (s, 3H).

Elemental analysis of a previous air dried sample corresponds well toone crystal water which is lost on further drying:

Measured Calculated % Air dried^(a) Deep dried^(b) 7 7 + H₂O 7 + 2H₂O C60.46 58.64 60.95 58.72 56.64 H 5.56 5.64 5.33 5.54 5.74 N 5.82 5.615.92 5.71 5.50 Cl 7.46 7.28 7.50 7.22 6.97 Pd <10 ppm <10 ppm ^(a)Airdried: equilibrated at 22° C. ^(b)Deep dried: equilibrated at 50° C.under 1 Hgmm for 24 hours.

Example 25

3-(2-(Diethylamino)ethyl)-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehydehydrochloride (2)

A mixture of3-(2-(diethylamino)ethyl)-7-hydroxy-4-methyl-2H-chromen-2-one (1 (312mg, 1.0 mmol) and hexamethylenetetramine (280 mg, 2.0 mmol) intrifluoroacetic acid (5 mL) was microwave irradiated for 20 min at 110°C. Upon cooling, the reaction mixture was evaporated. The residue wasdiluted with water (10 mL) and CH₂Cl₂ (30 mL), cooled to 0° C.,neutralized with NaHCO₃ solution and extracted with CH₂Cl₂. The organicphase was dried and HCl (1 mL, 2M in ether) was added to it. Evaporationand crystallization from a CH₂Cl₂/hexane mixture afforded the titleproduct. MS (ESI): 304 (M+H)⁺. ¹H NMR (δ, DMSO (2.5 ppm)): 10.45 (s,1H), 8.02 (d, 1H), 7.00 (d, 1H), 3.22 (q, 4H), 3.11 (m, 2H), 2.94 (m,2H), 2.46 (s, 3H), 1.24 (t, 6H).

Example 26

Step A 6-Hydroxy-2-oxo-1,2-dihydroquinoline-5-carbaldehyde (2)

A mixture of 6-hydroxyquinolin-2(1H)-one (1) (TCI:2,6-dihydroxyquinoline) (806 mg, 5.0 mmol) and hexamethylenetetramine(1.40 g, 10.0 mmol) in trifluoroacetic acid (6 mL) was microwaveirradiated for 20 min at 100° C. The reaction was run twice with twoparallels on a 5 mmol scale. Upon cooling, the two reaction mixtureswere washed into a 100 mL flask with MeOH (40 mL). The mixture wasevaporated to ˜10 mL and diluted with water (70 mL) with vigorousstirring. The precipitated product was filtered, washed with water anddried on air to afford 1.85 g (97%) title compound. MS (ESI): 190(M+H)⁺. ¹H NMR (δ, DMSO (2.5 ppm)): 11.84 (s, 1H, OH), 11.07 (s, 1H,NH), 10.61 (s, 1H, CHO), 8.86, 7.51, 7.24 and 6.63 (4d, 4×1H).

Step B 2-Chloro-6-hydroxyquinoline-5-carbaldehyde (3)

POCl₃ (973 μL, 10.4 mmol) was added dropwise to a DMF (5 mL) solution of6-hydroxy-2-oxo-1,2-dihydroquinoline-5-carbaldehyde (658 mg, 3.48 mmol)at 0° C. The mixture was stirred for 20 hours at 20° C. then cooled to0° C. Upon addition of ice water the product precipitated. It wasfiltered, washed with water and dried on air to afford 580 mg (88%) ofthe title compound. MS (ESI): 208 (M+H)⁺. ¹H NMR (δ, DMSO (2.5 ppm)):11.95 (s, 1H, OH), 10.70 (s, 1H, CHO), 9.38, 8.10, 7.67 and 7.55 (4d,4×1H).

Step C6-Hydroxy-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)quinoline-5-carbaldehyde(5)

A mixture of 2-chloro-6-hydroxyquinolin-5-carbaldehyde (3) (104 mg, 0.5mmol), 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (4) (198 mg,0.7 mmol) and K₂CO₃ (174 mg, 1.25 mmol) in a mixture of i-PrOH and water(6 mL 10:1) was purged with Argon for five minutes in a microwavevessel. A tablet of PdOAc₂(Sphos)₄ (Aldrich, Cat. No. 694088) was addedunder an Argon atmosphere then the vessel was sealed and irradiated for45 min at 165° C. Upon cooling, the reaction mixture was filteredthrough a silica plug using MeOH. The solution was evaporated andpurified by Flash chromatography using 0-5% MeOH in CH₂Cl₂. The productwas recrystallized from CH₂Cl₂/hexanes to afford the title compound. MS(ESI): 376 (M+H)⁺. ¹H NMR (δ, DMSO (2.5 ppm)): 10.74 (s, 1H), 9.44 8.25,7.21 and 7.49 (4d, 4×1H), 8.29 and 7.54 (2d, 2×2H), 3.64, 3.38, 2.41 and2.33 (4 broad s, 4×2H), 2.23 (s, 3H).

Example 27

6-hydroxy-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)quinoline-5-carbaldehyde(7)

A mixture of 2-chloro-6-hydroxyquinolin-5-carbaldehyde (3) (104 mg, 0.5mmol), 3-(4-methylpiperazine-1-carbonyl)phenylboronic acid (6) (198 mg,0.7 mmol) and K₂CO₃ (174 mg, 1.25 mmol) in a mixture of i-PrOH and water(6 mL 10:1) was purged with Argon for five minutes in a microwavevessel. A tablet of PdOAc₂(Sphos)₄ (Aldrich, Cat. No. 694088) was addedunder an Argon atmosphere then the vessel was sealed and irradiated for45 min at 165° C. Upon cooling, the reaction mixture was filteredthrough a silica plug using MeOH. The solution was evaporated andpurified by Flash chromatography using 0-5% MeOH in CH₂Cl₂. The productwas recrystallized from CH₂Cl₂/hexanes to afford the title compound. MS(ESI): 376 (M+H)⁺. ¹H NMR (δ, DMSO (2.5 ppm)): 10.74 (s, 1H), 9.44 (d,1H), 8.30 (dd, 1H), 8.27 (d, 1H), 8.24 (s, 1H), 8.23 (d, 1H), 7.61 (t,1H), 7.49 (d, 1H), 7.47 (dd, 1H), 3.60, 3.40, 2.40 and 2.30 (4 broad s,4×2H), 2.23 (s, 3H).

Example 286-Hydroxy-2-[4-(4-methyl-piperidine-1-carbonyl)-phenyl]-benzothiazole-7-carbaldehyde

Step A[4-(6-Hydroxy-benzothiazol-2-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone

2-Bromo-6-hydroxybenzothiazole (400 mg, 1.74 mmol),4-(4-methylpiperidine-1-carbonyl)phenylboronic acid (472 mg, 1.91 mmol),potassium phosphate (848 mg, 6.96 mmol) andtetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) were dissolvedin a mixture of 13.5 mL 2-ethoxyethanol and 1.5 mL water. The mixturewas stirred at 115° C. under argon for 2 h. The reaction mixture was letto reach room temperature then activated-carbon was added and stirredfor 20 min. The mixture was filtered, the solid was washed with ethanoland the combined filtrates were evaporated. The residue was purified bycolumn chromatography (Kieselgel 60) with chloroform as the eluent. Thecrude product was triturated with Et₂O, collected and air dried,affording the title compound (122 mg, 0.35 mmol, 20%).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 28a-1 —

BB_LCMS01(+) 353 3.598 100 n/a 28a-2 —

BB_LCMS01(+) 354 2.375  99 n/a

Step B6-Hydroxy-2-[4-(4-methyl-piperidine-1-carbonyl)-phenyl]-benzothiazole-7-carbaldehyde

A mixture of[4-(6-Hydroxy-benzothiazol-2-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone(120 mg, 0.34 mmol), hexamethylenetetramine (190 mg, 1.36 mmol) andtrifluoroacetic acid (2 mL) was stirred in a closed vessel under argonatmosphere at 120° C. for 1 h. The reaction was cooled to roomtemperature and 10 mL of water was added. The pH of the mixture wasadjusted to 8 by dropwise addition of saturated NaHCO₃ solution, andextracted with dichloromethane (3×15 mL). The combined organic layerswere dried (MgSO₄), filtered and evaporated. The residue was purified bycolumn chromatography on silica (Kieselgel 60), eluting withchloroform-methanol 99:1. The title compound (34 mg, 0.089 mmol, 26%)was obtained as pale yellow crystals.

¹H NMR (400 MHz, CDCl₃) δ ppm 11.20 (s, 1H), 10.35 (s, 1H), 8.13 (d,J=9.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 7.13 (d,J=9.3 Hz, 1H), 4.66 (br. s., 1H), 3.76 (br. s., 1H), 3.03 (br. s., 1H),2.80 (br. s., 1H), 1.81 (br. s., 1H), 1.57-1.72 (m, 2H), 1.07-1.35 (m,2H), 1.00 (d, J=6.5 Hz, 3H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 28-1 28a-1

BB_LCMS01(−) 381 3.645 100 98 28-2 28a-2

BB_LCMS01(+) 382 2.479  97 95

Example 296-Hydroxy-2-[5-(4-methyl-piperazine-1-carbonyl)-thiophen-2-yl]-benzothiazole-7-carbaldehyde

Step A 5-(6-Methoxy-benzothiazol-2-yl)-thiophene-2-carboxylic acid

2-Bromo-6-methoxy-benzothiazole (1.22 g, 5.00 mmol),2-carboxythiophene-5-boronic acid (860 mg, 5.00 mmol), sodium carbonate(2.65 g, 25.00 mmol) and tetrakis(triphenylphosphine)palladium (300 mg,0.25 mmol) were dissolved in a mixture of 80 mL N,N-dimethylformamideand 80 mL water. The mixture was stirred at 120° C. under argon for 2 h.The reaction mixture was evaporated and the residue was partitionedbetween 100 mL of water and 100 mL of dichloromethane. A considerableamount of white solid precipitated between the layers and was filteredoff and triturated with diethyl ether, affording the title compound (550mg, 1.89 mmol, 38%) as a white powder.

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 29a —

BB_LCMS01(+) 292 3.490 94 n/a

Step B 5-(6-Hydroxy-benzothiazol-2-yl)-thiophene-2-carboxylic acid

To dry tetrahydrofuran (30 mL), 1-methylpiperazine (834 μL, 756 mg, 7.56mmol), triethylamine (1.05 mL, 762 mg, 7.56 mmol)5-(6-Methoxy-benzothiazol-2-yl)-thiophene-2-carboxylic acid (550 mg,1.89 mmol), 1-hydroxybenzotriazole (510 mg, 3.78 mmol) and1-ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride (726 mg,3.78) were added sequentially. The mixture was stirred at roomtemperature overnight then was evaporated. The residue was suspended insaturated sodium bicarbonate (20 mL) and extracted with dichloromethane(3×20 mL). The combined organic layers were dried (Na₂SO₄), evaporatedand recrystallized from toluene. The title compound (399 mg, 1.070 mmol,57%) was isolated as a white powder.

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 29b 29a

BB_LCMS01(+) 374 2.708 94 n/a

Step C[5-(6-Hydroxy-benzothiazol-2-yl)-thiophen-2-yl]-(4-methyl-piperazin-1-yl)-methanone

To a solution of 5-(6-Hydroxy-benzothiazol-2-yl)-thiophene-2-carboxylicacid (375 mg, 1.00 mmol) in abs. dichloromethane (3 mL) stirred underargon at −78° C., boron tribromide (769 μl, 2.00 g, 8.00 mmol) was addedvia syringe and the mixture was stirred for 1 h and then allowed to warmto room temperature and stirred for 12 h. The reaction was quenched at−78° C. by addition of methanol (0.50 mL) and the mixture was for 1 hand allowed to warm to room temperature and stirred for 1 h. Thevolatiles were removed and the solid residue was recrystallized withethanol, filtered, washed with diethyl-ether and dried to give the titlecompound (295 mg, 0.82 mmol, 82%) as a gray solid.

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 29c 29b

BB_LCMS01(+) 360 2.346 95 n/a

Step D6-Hydroxy-2-[5-(4-methyl-piperazine-1-carbonyl)-thiophen-2-yl]-benzothiazole-7-carbaldehyde

A mixture of[5-(6-Hydroxy-benzothiazol-2-yl)-thiophen-2-yl]-(4-methyl-piperazin-1-yl)-methanone(290 mg, 0.81 mmol), hexamethylenetetramine (453 mg, 3.23 mmol) andtrifluoroacetic acid (3 mL) was stirred in a closed vessel under argonatmosphere at 120° C. for 1 h. The mixture was cooled to roomtemperature and 10 mL of water was added. The pH of the mixture wasadjusted to 8 by slow addition of a saturated NaHCO₃ solution, thenextracted with dichloromethane (3×20 mL). After drying (MgSO₄),filtration and evaporation of the solvent, the residue was purified bycolumn chromatography by ISCO on silica (Kieselgel 60) using achloroform-methanol gradient followed by trituration with diethyl ether.The title compound (23 mg, 0.059 mmol, 10%) was obtained as an orangesolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (s, 1H), 8.16 (d, J=9.0 Hz, 1H),7.81 (d, J=3.8 Hz, 1H), 7.46 (d, J=3.8 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H),3.63-3.70 (m, 4H), 2.34-2.43 (m, 4H), 2.23 (s, 3H).

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 29-1 29c

BB_LCMS01(+) 388 2.465 97 98

Example 306-Hydroxy-2-(4-isopropyl-piperazin-1-yl)-benzothiazole-7-carbaldehyde

Step A 2-(4-Isopropyl-piperazin-1-yl)-benzothiazol-6-ol

2-Bromo-6-hydroxybenzothiazole (345 mg, 1.5 mmol),1-isopropyl-piperazine hydrochloride (271 mg, 1.65 mmol) and drypotassium carbonate (828 mg, 6.00 mmol), were dissolved in 6 mL of dryN,N-dimethylformamide. The resulted pale brown solution was stirred at100° C. for 18 h in a closed vial. The reaction mixture was evaporated,suspended in 20 mL of water and extracted with dichloromethane (3×15mL). The combined organic layers were washed with saturated sodiumbicarbonate and brine, then dried over MgSO₄. After evaporation theresidue was purified by column chromatography (Kieselgel 60) usingchloroform-methanol 49:1 as the eluent. The title compound (76 mg, 0.27mmol, 18%) was obtained as a white solid.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 30a-1 —

BB_LCMS01(+) 278 1.345 87 n/a 30a-2 —

BB_LCMS01(+) 278 1.141 87 n/a 30a-3 —

BB_LCMS01(+) 318 0.452 93 n/a

Step B6-Hydroxy-2-(4-isopropyl-piperazin-1-yl)-benzothiazole-7-carbaldehyde

A mixture of 2-(4-Isopropyl-piperazin-1-yl)-benzothiazol-6-ol (76 mg,0.027 mmol), hexamethylenetetramine (153 mg, 1.10 mmol) andtrifluoroacetic acid (2 mL) was stirred in a closed vessel under argonatmosphere at 120° C. for 1 h. The mixture was cooled to roomtemperature then 10 mL of water was added. The pH of the mixture wasadjusted to 8 by portionwise addition of saturated NaHCO₃ solution, andextracted with dichloromethane (3×15 mL). After drying (MgSO₄),filtration and evaporation of the solvent, the residue was purified bycolumn chromatography (Kieselgel 60) using chloroform-methanol 49:1 aseluent followed by trituration with diethyl ether and n-hexane. Thetitle compound (14 mg, 0.040 mmol, 14%) was obtained as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.66 (br. s., 1H), 10.44 (s, 1H), 7.62(d, J=8.5 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 3.48-3.55 (m, 4H), 2.66-2.79(m, 1H), 2.53-2.59 (m, 4H), 0.99 (d, J=6.5 Hz, 6H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 30-1 30a-1

BB_LCMS01(+) 306 2.228 90 90 30-2 30a-2

BB_LCMS01(+) 306 2.629 95 95 30-3 30a-3

BB_LCMS01(+) 347 1.969 95 93

Example 31 4-(7-Formyl-6-hydroxy-1H-benzoimidazol-2-yl)-benzoic acidmethyl ester

Step A 4-(6-Methoxy-1H-benzoimidazol-2-yl)-benzoic acid methyl ester

4-Methoxybenzene-1,2-diamine (1.96 g, 14.2 mmol), 4-formylbenzoic acidmethyl ester (2.33 g, 14.2 mmol) and sodium bisulphite (1.55 g, 14.9mmol) were refluxed in methanol (50 mL) for 3 h, then evaporated todryness. The solid residue was partitioned between dichloromethane andwater. The organic layer was dried, evaporated and purified by columnchromatography, eluting with. The title compound (2.65 g, 9.40 mmol,66%) was obtained as a dark solid.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 31a-1 —

BB_LCMS01(+) 283 2.698 99 n/a 31a-2 —

BB_LCMS01(+) 283 2.693 100 n/a

Step B 4-(7-Formyl-6-methoxy-1H-benzoimidazol-2-yl)-benzoic acid methylester

A mixture of 4-(6-Methoxy-1H-benzoimidazol-2-yl)-benzoic acid methylester (1.50 g, 5.3 mmol), hexamethylenetetramine (1.50 mg, 10.60 mmol)and trifluoroacetic acid (12 mL) was stirred in a closed vessel under anargon atmosphere at 130° C. for 3 h. The resultant brown solution waspoured onto 250 mL of crushed ice. The mixture was extracted withchloroform-ethanol 95:5 (2×100 mL). The combined organic layers weredried (Na₂SO₄), and evaporated. The solid residue was purified by columnchromatography over silica (Kieselgel 60) using chloroform as the eluentto give title compound (350 mg, 1.13 mmol, 21%) yellow crystals.

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 31b-1 31a-1

BB_LCMS01(+) 311 3.287 100 n/a 31b-2 31a-2

BB_LCMS01(+) 311 3.218 60 n/a

Step C 4-(7-Formyl-6-hydroxy-1H-benzoimidazol-2-yl)-benzoic acid methylester

To a solution of 4-(7-Formyl-6-methoxy-1H-benzoimidazol-2-yl)-benzoicacid methyl ester (650 mg, 2.1 mmol) in abs. dichloromethane (30 mL) at−78° C., boron tribromide (1.20 mL, 3.20 g, 12.60 mmol) was addeddropwise and the mixture was stirred for 1 h, then overnight at roomtemperature. The yellow suspension was cooled to −78° C. and quenchedwith methanol (30 mL) followed by evaporation. The residue waspartitioned between saturated sodium bicarbonate (30 mL) and chloroform(30 mL). The organic phase was dried (Na₂SO₄) and evaporated. The titlecompound (360 mg, 1.22 mmol, 58%) was isolated as a light green solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.69 (br. s., 1H), 10.54 (s, 1H), 8.38(d, J=8.5 Hz, 2H), 8.09 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 6.87(d, J=8.8 Hz, 1H), 3.89 (s, 3H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 31-1 31b-1

BB_LCMS01(−) 295 3.100 98 98 31-2 31b-2

BB_LCMS01(−) 295 3.054 100 98

Example 32 4-(7-Formyl-6-hydroxy-1H-benzoimidazol-2-yl)-benzoic acid

4-(7-Formyl-6-hydroxy-1H-benzoimidazol-2-yl)-benzoic acid methyl ester(360 mg, 1.22 mmol) was dissolved in a mixture of dioxane (6 mL) and 1NNaOH (6 mL) and was stirred at 50° C. for 1 h. The mixture wasevaporated to half volume and acidified with glacial acetic acid. Theprecipitate was collected, washed with acetone and dried. The titlecompound (305 mg, 1.08 mmol, 89%) was isolated as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.75 (br. s., 1H), 10.57 (s, 1H), 8.33(d, J=8.5 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.8 Hz, 1H), 6.90(d, J=8.8 Hz, 1H).

The following compounds (includes title compound) were made by the aboveprocedure:

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 32-1 31-1

BB_LCMS01(+) 283 2.636 100 98 32-2 31-2

BB_LCMS01(+) 283 2.609 100 95

Example 335-Hydroxy-2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-3H-benzoimidazole-4-carbaldehyde

To dry tetrahydrofuran (5 mL), 1-methylpiperazine (69 μL, 63 mg, 0.62mmol), triethylamine (196 μL, 142 mg, 1.40 mmol),4-(7-Formyl-6-hydroxy-1H-benzoimidazol-2-yl)-benzoic acid (80 mg, 0.28mmol), 1-hydroxybenzotriazole (84 mg, 0.62 mmol) and1-ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride (120 mg,0.62) were added in the above order. The mixture was stirred at roomtemperature overnight. The resulted brown solution was suspended insaturated sodium bicarbonate (60 mL) and extracted with dichloromethane(3×20 mL). The combined organic layers were dried (Na₂SO₄), evaporatedand purified by column chromatography (Kieselgel 60), eluting withchloroform-methanol 9:1. The title compound (35 mg, 0.096 mmol, 34%) wasisolated as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.71 (br. s., 1H), 10.51 (br. s., 1H),8.28 (br. s., 2H), 7.83 (br. s., 1H), 7.53 (br. s., 2H), 6.87 (d, J=8.8Hz, 1H), 3.50 (br. s., 4H), 2.33 (br. s., 4H), 2.21 (s, 3H).

The following compounds (includes title compound) were made by the aboveprocedure:

EX- LCMS LCMS NMR AM- Made LCMS Rt purity purity PLE From Structure LCMSmethod Ion (min) (%) (%) 33-1 32-1

BB_LCMS01(+) 365 2.057 100 90 33-2 32-1

BB_LCMS01(+) 395 2.261 100 80 33-3 32-1

BB_LCMS01(+) 352 2.587 100 95

Example 34 (7-Formyl-6-hydroxy-1H-benzoimidazol-2-ylsulfanyl)-aceticacid

Step A (6-Methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethyl ester

6-Methoxy-1H-benzoimidazole-2-thiol (10.00 g, 55.56 mmol) was dissolvedin DMF (300 mL). NaH (2.44 g, 60 w/w % in mineral oil, 61.11 mmol) wasadded in small portions at room temperature. The resulted mixture wasstirred for one h then bromo-acetic acid ethyl ester (10.21g, 61.11mmol) was added. After 12 h the mixture was evaporated and the resultedslurry was diluted with HCl (340 mL, 2N) and was stirred for a 0.5 h atroom temperature then was filtered, washed with water and n-hexanerespectively. The title compound (14.70 g, 99%) was isolated as a paleyellow powder.

LCMS/BB_LCMS01(+)/: M+1=267, Rt: 2.586 min, pur: 99%

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 34a —

BB_LCMS01(+) 267 2.586 99 n/a

Step B (7-Formyl-6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acidethyl ester

A mixture of (6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethylester (14.70 g, 55.26 mmol), hexamethylenetetramine (15.47 g, 100.53mmol) and trifluoroacetic acid (61 mL) was stirred under argonatmosphere at 120° C. for 1 h. The solution was cooled to roomtemperature and water (950 mL) was added. This aqueous mixture wasextracted with EtOAc (3×200 mL). The combined organic layers were driedover Na₂SO₄ and evaporated. The title compound (1.432 g, 4.87 mmol, 9%)was obtained by column chromatography in 2 consecutive steps followed bytrituration with diethyl ether.

LCMS/BB_LCMS01(+)/: M+1=295, Rt: 3.084 min, pur: 97%

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 34b 34a

BB_LCMS01(+) 295 3.084 97 n/a

Step C (7-Formyl-6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid

(7-Formyl-6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethylester (1.432 g, 4.87 mmol) was dissolved in a mixture of 19.5 mL of 1Nsodium hydroxide and 15 mL of dioxane. The solution was stirred at 50°C. for 2 h, cooled to 0° C., and the pH was adjusted to 3.5 by dropwiseaddition of 6N HCl, keeping the temperature at 0° C. The precipitatedyellow solid was filtered, washed with ice cold water and dried. Thetitle compound (1.10g, 4.15 mmol, 85%) was isolated as a yellow powder.

LCMS/BB_LCMS01(−)/: M+1=265, Rt: 2.390 min, pur: 100%

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 34c 34b

BB_LCMS01(+) 267 2.384 100 n/a

Step D (7-Formyl-6-hydroxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid

To a solution of(7-Formyl-6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethylester (500 mg, 1.88 mmol) in abs. dichloromethane (40 mL) stirred underargon at −78° C., boron tribromide (723 μl, 1.88 g, 7.52 mmol) was addeddropwise and the mixture was warmed to room temperature and stirred for2 h. An additional portion of boron tribromide (723 μl, 1.88 g, 7.52mmol) was added at −78° C. and stirred for 2 h at room temperature. Themixture was quenched by slow addition of 120 mL of water. The mixturewas evaporated to dryness, suspended in boiling ethyl acetate, and thesolid was filtered off. The filtrate was evaporated and triturated withdiethyl ether. The title compound (220 mg, 0.87 mmol, 46%) was obtainedas a light orange powder.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.64 (br. s., 1H), 10.41 (s, 1H), 7.64(d, J=8.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.10 (s, 2H).

LCMS LCMS NMR Made LCMS Rt purity purity EXAMPLE From Structure LCMSmethod Ion (min) (%) (%) 34-1 34c

BB_LCMS01(+) 253 1.977 92 95

Example 35

IRE-1α Assay

A fusion protein comprising glutathione S transferase (GST) and humanIRE-1α (GST-IRE-1α) obtained from a 500 ml baculovirus-infected insectcell culture can be used to measure IRE-1α activity in vitro.

Five μl of a reaction mixture comprising 1× reaction buffer (5× reactionbuffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl₂), 3 mM DTT, and0.4% polyethylene glycol water is added to each well of 384 well plates.Twenty-five nanoliters of a 1 mM test compound solution are added totest wells. Three μl of a 128 ng/ml IRE-1α preparation are added to eachtest well and to positive control wells (final concentration 5.82ng/well). Negative control wells contain only reaction mixture and testcompound.

After spinning the plates at 1200 rpm for 30 seconds, 3 μl of an IRE-1αhuman mini-XBP-1 mRNA stem-loop substrate 5′-CAGUCCGCAGCACUG-3′ (SEQ IDNO:1), labeled with the fluorescent dye Cy5 at the 5′ end and Black HoleQuencher 2 (BH2) at the 3′ end, are added to each well of a controlplate. The plates are again spun at 1200 rpm for 30 seconds. Finalconcentrations for the assay are: 63 nM IRE-1α substrate, 5.82 ng IRE-1αprotein, and 2.5 μM test compound.

The plates are covered with lids and incubated for one hour at 30° C.The plates are then transferred to an ACQUEST™ microplate reader. Datais analyzed using data analysis software, and the percent activity ofIRE-1α is calculated.

Example 36

Determination of IC₅₀ for Inhibition of IRE-1α

IC₅₀ for inhibition of IRE-1α of compounds identified in Table 1 wasmeasured as described in EXAMPLE 35.

Example 37

Kinase Selectivity Assays

Compounds are assayed for their ability to inhibit 86 different kinasesat a concentration of 10 μM. The results of the assays demonstrate thatthese compounds are selective for IRE-1α.

Example 38

Cell-Based Assays

Human myeloma MM.1s cells are incubated with a compound for 1.25 hoursbefore stressing the cells with 2 mM dithiothreitol (DTT). After anadditional 45 minutes (2 hours total) with compound and DTT, the cellsare harvested with TRIZOL® (a mono-phasic solution of phenol andguanidine isothiocyanate), and total RNA is prepared as directed by themanufacturer (Invitrogen). Human XBP-1 is amplified by RT-PCR with thefollowing primers, which flank the 26 base unconventional intron excisedby IRE-1α:

(SEQ ID NO: 2) CCTGGTTGCTGAAGAGGAGG (forward) and (SEQ ID NO: 3)CCATGGGGAGATGTTCTGGAG (reverse).

In unstressed cells, IRE-1α is inactive and hence, the 26 base intron isleft in the XBP-1 mRNA. RT-PCR of unstressed (U) cells then generatesthe upper band. When cells are stressed (S) with the endoplasmicreticulum (ER) stressing agent DTT, IRE-1α is activated due toaccumulating unfolded protein and the resulting RT-PCR product is 26base pairs shorter. Increasing amounts of the compound blockIRE-1α-mediated XBP-1 splicing as demonstrated by a shift from a lowerband to an upper band. Compound potency reflects SAR in the in vitroenzyme assay.

Determination of Cellular EC₅₀ for IRE-1α Inhibitors

Compounds which pass specificity assays are assayed for cellular EC₅₀using endogenous XBP-1 splicing in myeloma cells. XBP-1 is regulatedthrough the excision of a 26 nucleotide intron from the XBP-1 mRNA bythe highly specific endoribonuclease activity of IRE-1α. This splicingevent induces a frame shift in the ORF of the C-terminus of XBP-1leading to the translation of the larger 54 kD active transcriptionfactor rather than the inactive 33 kD form. This splicing event is usedto measure IRE-1α activity on XBP-1 mRNA in cells and tissues.

Briefly, compounds are incubated in the presence or absence of an ERstress agent (e.g., DTT), and the ratio of XBP-1u (unspliced) to XBP-1s(spliced) is quantified by RT-PCR. The ED₅₀ is determined as the 50%XBP-1s to total XPB-1 levels. Compounds which have EC₅₀s equal to orbelow 10 μM are used in standard apoptosis assays, including Annexin Vstaining and CASPASE-GLO®.

Proliferation assays using myeloma cell lines (U266, RPMI8226 and MM.1s)are used to determine ED₅₀. Compounds are used as single agents and incombination with other chemotherapeutic drugs. IRE-1α inhibitorcompounds inhibit the proliferation of RPMI8226 myeloma cells, whichhave endogenous activation of the pathway and are further induced by theaddition of bortezomib. When an IRE-1α inhibitor compound is used incombination with MG-132, increased apoptosis is observed with U266myeloma cells.

Example 39

Animal Model/Preclinical Validation Studies

The preclinical validation strategy employs a set of animal modelsrepresenting normal tissues under chemical stress and multiple myelomaxenographs. The normal animal model is employed as a surrogate modelwhere dose-related on-target activity of compounds can be confirmed intissues sensitive to standard UPR inducing agents such as tunicamycin(Wu et al., Dev Cell. 2007 September; 13(1d):351-64). Normal mousetissues are not under ER stress, and therefore the XBP-1 mRNA remains asthe inactive, unspliced form. Upon induction with tunicamycin, tissuesinduce active XBP-1 mRNA splicing, and this activity is suppressed byIRE-1α inhibitors. This on-target ER stress animal model is a usefulscreening and early pharmacokinetic tool.

Antibody production is evaluated in a second surrogate model. However,in cell-based models, IRE-1α inhibitors have been shown to potentlyinhibit antibody production.

Final efficacy studies are performed in myeloma xenograft models, asdescribed below.

Example 40

RPMI8226 Xenograft Efficacy Model

SCID mice are evaluated for their ability to support implantation ofdesired tumor cells in support of model development andcharacterization. Mice are injected intravenously (5) or implantedeither subcutaneously (SC) or intraperitoneally (IP). To generate arelevant animal model mimicking human disease, it is desirable that allthree approaches are evaluated for improved implantation rates andrelevant disease progression, as is well known in the art. SC injectionsprovide an easy way to measure tumor growth and efficacy, and IV and IPinjections represent a more physiologically relevant model of humantumor spread. SC injections are given primarily in the flank, while IVinjections are administered in the tail vein. Mice are manuallyrestrained for SC and IP injections, and a Broome mouse restrainer isused for IV injections.

Example 41

Evaluation of IRE-1α Inhibitor Compounds in a Xenograft Efficacy Model

SCID mice are implanted with tumor cells (human RPMI8226 myeloma cells)via IP, IV or SC routes based on the results from the xenograft modeldevelopment studies (above). Mice are treated with compound or mocktreated (vehicle) for a period of up to 4-5 weeks. Compoundadministration can be via IV, IP, PO or SC routes. In some cases,tunicamycin is administered via IP injection in order to stimulatestress in the animal. This stress mimics the stress an animal mayundergo during times of tumor growth. The tunicaymycin injection mimicstumor growth during times of stress and permits evaluation of biomarkerswhich indicate the effectiveness of a compound (such as XBP-1 splicing)by RT-PCR, immunohistochemistry, or Western blots.

Mice are monitored for tumor growth, regression and general health.Tumors are collected and characterized by immunohistochemistry and/orFACS analysis. Tumor growth is measured by calipers, ultrasound, or byabdominal lavage. Biomarkers in the blood or tumor can evaluated(primarily XBP-1 splicing).

In some experiments, blood samples are collected at various time pointsduring the dosing (i.e., day 1 or week 4 etc.) to evaluate thepharmacokinetic profile. The time points of blood collection varydepending on the pharmacokinetic properties of the drug being tested.The volume of blood sample is 100 microliters/per time point, and miceare bled twice after drug administration within a 24 hour period viaretro-orbital sinus. If the same mouse is used, blood samples arecollected once from each eye during 24 hours.

Tumor cells are cultured and injected IP, IV (tail vein) or SC (flank)in the mouse using a 21G needle in a volume of approx 100 μL. Mice aretreated with compounds or vehicle alone as a control by IV, IP, SC or POroutes 5 days per week for up to 4-5 weeks. Blood is collected viaretroorbital bleed (100 μl) at 2 time points (different eyes). Theendpoint of the study depends on the overall health of the mice: whilemice are euthanized at the end of 4-5 weeks in most studies, mice aremaintained until day 40 in a few studies if their general health willallow. The reason for maintaining studies for 40 days is to determine ifthe tested compounds have a long term effect on inhibiting tumor growth.Euthanization of mice in which tumor regression is observed will dependon the experimental design. In screening mode, the experiment will endwith tumors in the control/untreated group reach 1.5 cm, are ulceratedor when loss of motility is observed in that group. In follow upexperiments, mice in which tumor regression is observed may bemaintained longer, until they show signs of tumor growth of ill health.

Therapeutic dosing with bortezomib 0.75 mg/kg IV twice weekly of SCIDmice bearing human myeloma RPMI8226 tumor xenografts resulted insuppression of tumor growth. However, after cessation of bortezomibtherapy, tumors often recurred and grew into large masses. Therefore,mice will be treated in combination as with both bortezomib (asindicated) and twice daily with 10-60 mg/kg IRE-1α/XBP-1 inhibitors suchas compound 17-1 by oral, IP or IV administration. Compounds whichreduce the incidence of tumor recurrence are identified.

Example 42

Combination Therapies

The spliced form of XBP-1, as a homodimer and heterodimer with ATF-6,transcriptionally regulates genes involved in adapting to ER stress (Wuet al., Dev Cell. 2007 September; 13(1d):351-64). Many of thesedownstream targets are major chaperones, co-chaperones and ERADcomponents of the ER. Chaperones such as GRP78 and GRP94 are stable andlong lived proteins with half lives on the order of days (Wu et al., DevCell. 2007 September; 13(1d):351-64). Therefore, treatment of cancerwith an IRE-1α/XBP-1 inhibitor may require up to 5 to 6 days oftreatment in each cycle.

In some embodiments, combination therapy given in cycles such as withproteasome inhibitors involves giving the patient 2 days of pretreatmentwith IRE-1α/XBP-1 inhibitor and then simultaneously with thechemotherapeutic agent until a pharmacodynamic effect is achieved(typically 24 hours post bortezomib infusion). Bortezomib is typicallyadministered on three week cycles, every 1, 4, 8 and 11 days (of 21).Dosing is 1.3 mg/m² by IV administration. IRE-1α/XBP-1 inhibitors can beadministered 2 day prior and 24 hours post infusion of bortezomib at 10to 100 mg/kg by the IV or oral route once, twice or three times dailydepending on the PK/PD relationship.

A similar protocol can be employed with Hsp90 and or HDAC inhibitors.Alternatively, both agents are administered simultaneously for theduration of each cycle depending on the PK/PD relation of the inhibitor.IRE-1α/XBP-1 inhibitors can be given to breast cancer patients incombination with Tamoxifen (Gomez et al., FASEB J. 2007 December;21(2):4013-27) or in combination with Sorafinib to various other cancersincluding kidney carcinoma and hepatocellular carcinoma (Rahmani et al.,Mol Cell Biol. 2007 August; 27(15):5499-513).

In general, because many kinase inhibitors often are not selective ontheir targeted kinase and often affect many additional kinases; they maycause non-specific cellular stress which may activate the UPR.Therefore, combination approaches may be useful using IRE-1α/XBP-1inhibitors as sensitizing agents.

Example 43

Inhibition of RIDD-Targeted Degradation

a. Experimental Procedures

Cell Culture.

RPMI 8226 cells were grown in monolayer culture using Dulbecco'sModified Eagle Medium (DMEM) supplemented with 10% fetal calf serum(FCS) at 37° C. and 5% CO₂. Compounds were kept as 10 mM stock in DMSOat −20° C. and diluted in medium to 10 μM. Thapsigargin (Tg) wasresuspended in DMSO and diluted in medium.

RT-qPCR.

Procedures for measuring XBP-1s and XBP-1u mRNAs have been describedpreviously (Volkmann et al., J. Biol. Chem. 286, 12743-55, 2011).Briefly, total RNA was harvested from cells or tissue using TRIZOL®(Invitrogen) according to the manufacture's procedures. After ethanolprecipitation and resuspension of the RNA, RIBOGREEN® (Invitrogen) wasused to quantify the yield- and normalize the RNA concentration in thesource tube containing isolated RNA. RT-PCR was performed by oligo dTpriming, SUPERSCRIPT® II (Invitrogen) and reverse transcription usingthe AMPLITAQ GOLD® Kit (Applied Biosystems) according to themanufacturer's protocols. Primers for human XBP-1 were

(forward, SEQ ID NO: 2) 5'-CCTGGTTGCTGAAGAGGAGG-3′ and(reverse, SEQ ID NO: 3) 5'-CCATGGGGAGATGTTCTGGAG-3′.

All DNA oligos were purchased from IDT DNA Technologies. PCR reactionswere run on a Bio-Rad PTC-100® 96-well thermocycler; heating at 94° C.for 30 seconds, annealing at 58° C. for 30 seconds polymerizing at 72°C. for 30 seconds for 35 cycles.

The same RNA preparations were used to evaluate levels of CD59 and Blos1by RT-qPCR. CD59 primers were and the probe and primer sequences were

(SEQ ID NO: 4) CD59 224s: CCAGTTGGTGTAGGAGTTGAGACC; (SEQ ID NO: 5)CD59 354a: AGGCTATGACCTGAATGGCAGA; and (SEQ ID NO: 6)CD59ap: CAGCCAGGACGAGCAGCAGCCCG.

Blos1 probes were commercially available from Applied Biosciences(Hs00155241_m1).

b. Results

Low levels of IRE-1α activation where observed in unstressed human RPMI8226 plasmacytoma cells as demonstrated small amounts of XBP-1s relativeto XBP-1u (FIG. 1). Treatment of RPMI cells for 2 hours with 300 nMThapsigargin (Tg) induced near complete conversion of XBP-1u to XBP-1sand 10 uM compound inhibited this completely (FIG. 1). When compound Bwas added in combination with Tg for the 2, 4, 6, 8, 16 and 24 hours,complete inhibition of XBP-1s with repopulation of XBP-1u was observed.RNA samples from this experiment were subjected RT-qPCR using specificprimers for CD59 and Blos1. Inhibition of RIDD targeted degradation ofBlos1 (Hollien, 2009) and CD59 (Oikawa, 2007) was observed by RT-qPCR.(FIG. 2).

Example 44

Measurement of XBP-1 Slicing Inhibition in the Livers and Kidneys ofCB17 SCID Mice in Response to Tunicamycin and Subsequent Treatment withan IRE-1α Inhibitor

CB17 SCID mice were treated with 1 mg/kg tunicamycin by intraperitoneal(IP) injection at time 0 (T=0). Two hours later, compound A formulatedin 10% hydroxy beta propyl cyclo dextran HBPCD was administered by IPinjection. Doses were 50 mg/kg, 25 mg/kg and 10 mg/kg (4 mice in eachgroup). Mice were sacrificed two hours later (4 hours from T=0), and thedesignated organs were harvested (FIG. 3A).

RT-PCR analysis was performed using murine-specific XBP-1 primers fromtotal RNA harvested from specified organs. The results are shown in FIG.4B. Tunicamycin alone induces XBP-1 spliced (XBP-1s) relative to PBStreated mice. Dose response for target inhibition (XBP-1s) can beobserved with increasing doses of compound A administered IP in both theliver and kidney. Each lane represents an individual mouse where RNA washarvested and RT-PCR was performed. Method of RNA extraction and RT-PCRanalysis is described in Volkmann et al., J. Biol. Chem. 286, 12743-55,2011.

The experiment was repeated using intravenous (IV) administration ofcompound A (50 mg/kg, 25 mg/kg and 10 mg/kg) and oral administration ofcompound A (100 mg/kg, 50 mg/kg or 25 mg/kg). The results are shown inFIGS. 4A and 4B, respectively.

Example 45

Inhibition of XBP-1 Splicing in the Tumors of RPMI 8226 Human MyelomaCells in Tumor Bearing SCID Mice by Intraperitoneal Administration of anIRE-1α Inhibitor

Mice were implanted subcutaneously with 10⁷ RPMI8226 cells on day 0.After 32 days of tumor growth, mice were treated with 100 mg/kg compoundB by IP administration. After 3, 6 and 24 hours of exposure, tumors wereharvested and RNA was prepared (FIG. 5A). RT-PCR amplification of XBP-1was performed using human specific primers (Volkmann et al., J. Biol.Chem. 286, 12743-55, 2011) and splicing was analyzed by agarose gelelectrophoresis. Three tumors for each of the time points were analyzedagainst untreated, 3 tumors, and 2 vehicle treated tumors (FIG. 5B).Target inhibition was observed for all 3 time points up to 24 hours whencompared to endogenous splicing levels in control groups.

Example 46

Inhibition of XBP-1 Splicing in the Tumors of RPMI 8226 Human MyelomaCells in Tumor-Bearing SCID Mice by Oral Dosing with an IRE-1α Inhibitor

Mice were implanted with 10⁷ RPMI8226 cells subcutaneously on day 0.After 28 days of tumor growth, mice were treated with 200 mg/kg, 100mg/kg, 50 mg/kg and 25 mg/kg compound Y by oral dosing. After 4 hours ofexposure, tumors were harvested and RNA was prepared (FIG. 6A). RT-PCRamplification of XBP-1 was performed using human specific primers(Volkmann et al., J. Biol. Chem. 286, 12743-55, 2011) and splicing wasanalyzed by agarose gel electrophoresis. Four tumors for each dose groupwere analyzed against 4 untreated control tumors (FIG. 6B). Targetinhibition was observed for the 3 higher dose groups: 200, 100 and 50mg/kg while the lowest dose group, 25 mg/kg was comparable to endogenoussplicing levels in the control group.

Example 47

Synthesis of ethyl 4-bromo-2-methyl-3-oxobutanoate

The solution of Br₂ (58.0 g, 364.5 mmol) in CHCl₃ (50 mL) was addeddropwise to the solution of compound 1 (50.0 g, 347.2 mmol) in CHCl₃(320 mL) at 0° C. Then the reaction mixture was allowed to warm slowlyto RT and stirred for 16 h. Air was bubbled to the reaction mixture atRT for 2 h. The reaction mixture was diluted with DCM (300 mL), washedwith sat. Na₂SO₃ (150 mL) and brine (100 mL×2). The organic layer wasdried over Na₂SO₄, filtered, concentrated, afforded crude compound 2 (50g) as light yellow oil without further purification. The crude productwas stored in fridge below 0° C.

Synthesis of4-(bromomethyl)-7-hydroxy-6-methoxy-3-methyl-2H-chromen-2-one

Compound 2 (19.0 g, 85.71 mmol) and compound 3 (10.0 g, 71.42 mmol) wereadded to CH₃SO₃H (80 mL) at RT. The reaction mixture was stirred at RTfor 16 h, then poured into ice-water (300 mL), extracted with EA (100mL×3). The combined EA was washed with brine, dried over Na₂SO₄,filtered, concentrated, purified by silica gel column (PE:EA=2:1),afforded 5.6 g of the crude compound 4. Then the crude product wastriturated with EA, afforded compound 4 (2.5 g, 9.7%) as white solid.

Synthesis of Compound 5

Compound 4 (1 eq) was added to MeCN. The solution of amine (2.5 eq) inMeCN was added dropwise at RT and stirred for 16 h. The reaction mixturewas concentrated. The residue was diluted with H₂O, extracted with DCM.The combined DCM was dried over Na₂SO₄, filtered, concentrated, affordedcrude compound 5 without further purification.

Synthesis of Compound 6

Compound 5 (1 eq) and HMTA (4 eq) were added to TFA. The mixture washeated to 90° C. for 2.5 h. After cooled to RT, the reaction mixture wasconcentrated, purified by prep-HPLC afforded compound 6.

7-Hydroxy-6-methoxy-3-methyl-4-(morpholinomethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure at 45.7% yield. ¹HNMR (CDCl₃, 400MHz): δ 12.43 (s, 1H, OH), 10.59 (s, 1H, CHO), 7.75 (s, 1H, ArH), 3.93(s, 3H, ArOCH₃), 3.68-3.66 (m, 6H), 2.56-2.53 (m, 4H), 2.26 (s, 3H,CH₃). MS [ESI, MH⁺]: 334.1

4-((Dimethylamino)methyl)-7-hydroxy-6-methoxy-3-methyl-2-oxo-2H-chromene-8-carbaldehydehydrochloride was obtained by the above procedure at 22% yield. ¹HNMR(DMSO-d6, 400 MHz): δ 10.45 (s, 1H, CHO), 7.58 (s, 1H, ArH), 4.68 (s,2H, NCH₂), 4.00 (s, 3H, OCH₃), 2.86 (s, 6H, 2CH₃), 2.25 (s, 3H, CH₃). MS[ESI, MH⁺]: 292.1

Example 48

Synthesis of4-(bromomethyl)-7-hydroxy-5-methoxy-3-methyl-2H-chromen-2-one

Compound 2 (38.0 g, 171.1 mmol) was added dropwise to the solution ofcompound 7 (20.0 g, 142.8 mmol) in H₃PO₄ (200 mL) at 0° C. The reactionmixture was warmed slowly to RT and stirred for 16 h, then poured intoice-water (500 mL), extracted with EA (200 mL×3). The combined EA waswashed with sat. NaHCO₃, dried over Na₂SO₄, filtered, concentrated. Thecrude product was purified by silica gel column (PE:EA=3:1), then washedwith DCM, afforded crude4-(bromomethyl)-7-hydroxy-5-methoxy-3-methyl-2H-chromen-2-one (8 g, 55%purity) without further purification.

Synthesis of Compound 9

Compound 8 (1 eq) was added to MeCN. The solution of amine (2.5 eq) inMeCN was added dropwise at RT and stirred for 16 h. The reaction mixturewas concentrated. 1N HCl was added to the residue, stirred for 15 min.The undissolved material was removed by filtration. The filter waswashed with DCM, then basified by saturated NaHCO₃, extracted with DCM.The combined DCM was dried over Na₂SO₄, filtered, concentrated, affordedcompound 9 as light green solid.

Synthesis of Compound 10

Compound 9 (1 eq) and HMTA (4 eq) were added to AcOH. The mixture washeated to 120° C. for 2 h. After cooled to RT, the reaction mixture wasconcentrated, purified by prep-HPLC and prep-TLC, afforded compound 10as yellow solid.

7-Hydroxy-5-methoxy-3-methyl-4-(morpholinomethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure at 19.6% yield. ¹HNMR (CDCl₃, 400MHz): δ 12.57 (s, 1H, OH), 10.41 (s, 1H, CHO), 6.30 (s, 1H, ArH), 3.94(s, 3H, ArOCH₃), 3.83 (s, 2H, CH₂), 3.61 (br, 4H, 2CH₂), 2.48 (br, 4H,2CH₂), 2.24 (s, 3H, CH₃). MS [ESI, MH⁺]: 334.1.

4-((Dimethylamino)methyl)-7-hydroxy-5-methoxy-3-methyl-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure at 20% yield. ¹HNMR (CDCl₃, 400MHz): δ 12.54 (br, 1H, OH), 10.40 (s, 1H, CHO), 6.30 (s, 1H, ArH), 3.99(s, 3H, ArOCH₃), 3.78 (s, 2H, CH₂), 2.29 (s, 6H, 2CH₃), 2.24 (s, 3H,CH₃). MS [ESI, MH⁺]: 292.1.

Example 49

Synthesis of ethyl 4-methoxy-3-oxobutanoate

NaH (7.71 g, 192.7 mmol) was suspended in DMF (110 mL). The solution ofMeOH (2.64 g, 82.5 mmol) in DMF (55 mL) was added dropwise at 0° C.After that, the mixture was stirred at 0° C. for 30 min. The solution ofcompound 1 (9.54 g, 57.9 mmol) in DMF (55 mL) was added dropwise at 0°C., then the reaction mixture was allowed to warm slowly to RT andstirred for 16 h. The reaction mixture was diluted with 1N HCl (400 mL),extracted with MTBE (250 mL×3). The combined organic layer was washedwith H₂O (200 mL×5), dried over Na₂SO₄, filtered, concentrated, purifiedby silica gel column (PE:EA=10:1) afforded ethyl4-methoxy-3-oxobutanoate (1.4 g, 15.1%) as light yellow oil.

Synthesis of 7-hydroxy-6-methoxy-4-(methoxymethyl)-2H-chromen-2-one

Compound 2 (1.50 g, 3.61 mmol) and compound 3 (1.24 g, 8.85 mmol) wereadded to CH₃SO₃H (15 mL) at RT. The reaction mixture was stirred at RTfor 16 h, then poured into ice-water (100 mL), extracted with EA (30mL×3). The combined EA was washed with sat. NaHCO₃, dried over Na₂SO₄,filtered, concentrated, purified by silica gel column (PE:EA=3:1)7-hydroxy-6-methoxy-4-(methoxymethyl)-2H-chromen-2-one (620 mg, 27.9%)as white solid.

Synthesis of7-hydroxy-6-methoxy-4-(methoxymethyl)-2-oxo-2H-chromene-8-carbaldehyde

Compound 4 (520 mg, 2.21 mmol) and HMTA (1230 mg, 8.78 mmol) were addedto TFA (30 mL). The mixture was heated to reflux for 3 h. After cooledto RT, the reaction mixture was concentrated, purified by pre-HPLC,afforded7-hydroxy-6-methoxy-4-(methoxymethyl)-2-oxo-2H-chromene-8-carbaldehyde(200 mg, 34.2%) as yellow solid. ¹HNMR (CDCl₃, 400 MHz): δ 12.55 (s, 1H,OH), 10.61 (s, 1H, CHO), 7.20 (s, 1H, ArH), 6.43 (s, 1H, ═CH), 4.57 (s,2H, OCH₂), 3.95 (s, 3H, ArOCH₃), 3.50 (s, 3H, OCH₃). MS [ESI, MH⁺]:265.2.

Example 50

Synthesis of Compound 6

EtONa (1.48 g, 21.87 mmol) was suspended in EtOH (35 mL). The solutionof compound 2 (3.50 g, 21.87 mmol) in EtOH (15 mL) was added dropwise atRT and stirred for 30 min. The solution of Br(CH₂)₂COOEt (3.93 g, 21.87mmol) in EtOH (15 mL) was added dropwise and stirred at RT for 16 h. Thereaction was quenched with 2 N HCl (10 mL), concentrated. The residuewas diluted with H₂O (50 mL), extracted with DCM (25 mL×3). The combinedDCM was dried over Na₂SO₄, filtered, concentrated, afforded crudecompound 6. (5.4 g) as yellow oil, without further purification.

Synthesis of Compound 7

Compound 6 (5.4 g, 20.76 mmol) and compound 3 (2.32 g, 8.85 mmol) wereadded to CH₃SO₃H (55 mL) at RT. The reaction mixture was stirred at RTfor 16 h, then poured into ice-water (300 mL), extracted with EA (100mL×3). The combined EA was washed with sat. NaHCO₃, dried over Na₂SO₄,filtered, concentrated, purified by silica gel column (PE:EA=3:1),afforded compound 7 (3.0 g, 42.9%) as white solid.

Synthesis of Compound 8

Compound 7 was added to amine and the reaction mixture was stirred at120° C. for 16 h. LC-MS showed that the starting material was almostconsumed completely. The solvent was removed under vacuum. The residuewas purified by silica gel column, afforded compound 8.

Synthesis of Compound 9

Compound 8 (1 eq) and HMTA (4 eq) were added to TFA. The mixture washeated to reflux for 2 h. After cooled to RT, the reaction mixture wasconcentrated, purified by prep-HPLC, afforded compound 9 as yellowsolid.

3-(8-formyl-7-hydroxy-6-methoxy-4-(methoxymethyl)-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 26.7% yield. ¹HNMR(CDCl₃, 400 MHz): δ12.47 (s, 1H, OH), 10.58 (s, 1H, CHO), 7.44 (s, 1H,ArH), 5.84 (br, 1H, NH), 4.72 (s, 2H, OCH₂), 3.94 (s, 3H, ArOCH₃), 3.46(s, 3H, OCH₃), 3.40-3.39 (m, 4H, 2CH₂), 3.29 (s, 3H, OCH₃), 3.03 (t,J=7.2 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H). MS [ESI, MH⁺]: 394.2.

7-Hydroxy-6-methoxy-4-(methoxymethyl)-3-(3-morpholino-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 12.7% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.44 (s, 1H, OH), 10.58 (s, 1H, CHO), 7.44 (s, 1H,ArH), 4.76 (s, 2H, OCH₂), 3.94 (s, 3H, ArOCH₃), 3.66-3.63 (m, 4H, 2CH₂),3.59-3.58 (m, 2H, CH₂), 3.50-3.49 (m, 2H, CH₂), 3.49 (s, 3H, OCH₃), 3.02(t, 2H, J=7.2 Hz, CH₂), 2.65 (t, 2H, J=7.2 Hz, CH₂). MS [ESI, MH⁺]:406.2

3-(8-Formyl-7-hydroxy-6-methoxy-4-(methoxymethyl)-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)propanamideas obtained by the above procedure from amine A5. 37.9% yield. ¹HNMR(CDCl₃, 400 MHz): δ10.58 (s, 1H, CHO), 7.44 (s, 1H, ArH), 4.72 (s, 2H,CH₂), 3.94 (s, 3H, ArOCH₃), 3.73 (br, 4H, 2CH₂), 3.46 (s, 3H, OCH₃),3.35 (br, 2H, CH₂), 3.04 (t, J=7.2 Hz, 2H, CH₂), 2.53-2.50 (m, 8H); MS[ESI, MH⁺]: 449.2

Example 51

Synthesis of5-(7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)thiophene-2-carboxylicacid

Compound 1 (15 g, 46 mmol), the boric acid (8.7 g, 50.6 mmol), Pd(PPh₃)₄(1.88 g, 2.3 mmol), Na₂CO₃ (12.1 g, 115 mmol) were added to DMF (250mL). The reaction mixture was degassed with N₂ for three times, and thenheated to 90° C. for 16 h. After cooled to RT, the solvent wasconcentrated, the residue was dissolved in sat Na₂CO₃ (150 mL). Theaqueous was washed with DCM (100 mL×4), and then acidified by con. HClto pH to ˜4. The result precipitate was collected by filtration,triturated with hot EA (50 mL), afforded compound 2 (6.5 g, 42%) asyellow solid. ¹HNMR (DMSO-d6, 400 MHz): δ 10.55 (s, 1H), 7.71 (d, J=4.0Hz, 1H), 7.24 (s, 1H), 7.19 (d, J=4.0 Hz, 1H), 6.86 (s, 1H), 3.88 (s,3H), 2.45 (s, 3H).

Synthesis of Compound 3

Compound 2 (1 eq), HATU (1.5 eq) and Et₃N (2.5 eq) were added to dryDMF. The mixture was stirred at RT for 30 min, then amine (1.5 eq) wasadded. The reaction mixture was stirred at RT overnight. 2N HCl wasadded, later extracted with DCM. The combined DCM was washed withsaturated NaHCO₃, dried over Na₂SO₄, filtered, concentrated, purified bysilica gel column, afforded compound 3.

Synthesis of Compound 4

Compound 3 (1 eq) and HMTA (4 eq) were added to TFA. The mixture washeated to reflux for 30 min. After cooled to RT, the reaction mixturewas concentrated, purified by prep-HPLC, afforded compound 4.

7-Hydroxy-6-methoxy-4-methyl-3-(5-(morpholine-4-carbonyl)thiophen-2-yl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 31% yield. ¹HNMR(DMSO-d6, 400 MHz): δ 10.46 (s, 1H), 10.38 (s, 1H), 7.53 (s, 1H), 7.44(d, J=3.6 Hz, 1H), 7.17 (d, J=3.6 Hz, 1H), 3.94 (s, 3H), 3.67-3.64 (m,8H), 2.48 (s, 3H). ¹HNMR (CDCl₃, 400 MHz): δ12.57 (s, 1H), 10.63 (s,1H), 7.31 (d, J=3.6 Hz, 1H), 7.23 (s, 1H), 7.06 (d, J=3.6 Hz, 1H), 3.98(s, 3H), 3.81-3.74 (m, 8H), 2.48 (s, 3H). MS [ESI, MH⁺]: 430.1.

7-Hydroxy-6-methoxy-4-methyl-3-(5-(4-methylpiperazine-1-carbonyl)thiophen-2-yl)-2-oxo-2H-chromene-8-carbaldehydehydrochloride was obtained by the above procedure from amine A3. 34%yield. ¹HNMR (MeOD, 400 MHz): δ 7.48 (d, J=4.0 Hz, 1H), 7.23 (s, 1H),7.13 (d, J=4.0 Hz, 1H), 6.02 (s, 1H), 4.66-4.62 (m, 2H), 3.94 (s, 3H),3.61-3.52 (m, 4H), 3.25-3.19 (m, 2H), 2.97 (s, 3H), 2.50 (s, 3H).

5-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)thiophene-2-carboxamidehydrochloride was obtained by the above procedure from amine A5. 22%yield. ¹HNMR (MeOD, 400 MHz): δ7.73 (d, J=4 Hz, 1H), 7.27 (s, 1H), 7.14(d, 4 Hz, 1H), 6.03 (s, 1H), 4.11-4.07 (m, 2H), 3.95 (s, 3H), 3.82-3.76(m, 4H), 3.70-3.67 (m, 2H), 3.43-3.40 (m, 2H), 3.25-3.21 (m, 2H), 2.50(s, 3H). ¹HNMR (DMSO, 400 MHz, T=273+80K): δ10.49 (s, 1H), 8.88 (t,J=6.0 Hz, 1H), 7.90 (d, J=4 Hz, 1H), 7.55 (s, 1H), 7.18 (d, J=4 Hz, 1H),3.95 (s, 3H), 3.94-3.92 (m, 4H), 3.74-3.69 (m, 2H), 3.34-3.31 (m, 4H),3.31-3.10 (m, 2H), 2.48 (s, 3H). MS [ESI, MH⁺]: 473.2.

Example 52

Synthesis of N-(2,4-dimethoxyphenyl)-2,2,2-trifluoroacetamide

Compound 1 (38 g, 249.6 mmol) and pyridine (21.7 g, 275.0 mmol) weredissolved in DCM (750 mL). (CF₃C0)₂O (57.7 g, 275.0 mmol) was addeddropwise at 0° C. After that the reaction mixture was stirred at RT for16 h. The reaction mixture was diluted with DCM (500 mL), washed with 1NHCl, concentrated. The residue was purified by silica gel column(PE:EA=10:1), afforded compound 2 (45 g, 72%) as white solid.

Synthesis of N-(2,4-dimethoxyphenyl)-2,2,2-trifluoro-N-methylacetamide

NaH (2.2 g, 90.3 mmol) was suspended in DMF (25 mL), cooled to −20° C.The solution of compound 2 (15 g, 60.2 mmol) in DMF (50 mL) was addeddropwise and stirred 0° C. for 1 h. MeI (17.1 g, 120.4 mmol) was addeddropwise at −20° C., then stirred at RT for another 1 h. The reactionmixture was quenched with H₂O, extracted with EA, dried over Na₂SO₄,filtered, concentrated. The residue was purified by silica gel column(PE:EA=3:1), afforded compound 3 (14 g, 88%) as white solid.

Synthesis of N-(2,4-dihydroxyphenyl)-2,2,2-trifluoro-N-methylacetamide

Compound 3 (8 g, 30.4 mmol) was dissolved in DCM (80 mL), cooled to −60°C. The solution of BBr₃ (30.4 g, 121.6 mmol) in DCM (40 mL) was added at−60° C. After that, the reaction mixture was stirred at RT for 1 h. Thenthe reaction was quenched with H₂O, extracted with DCM. The combined DCMwas dried over Na₂SO₄, filtered, concentrated. The residue was purifiedby silica gel column (PE:EA=1:1), afforded compound 4 (6.1 g, 85.9%) aswhite solid.

Synthesis of ethyl3-(7-hydroxy-4-methyl-6-(methylamino)-2-oxo-2H-chromen-3-yl)propanoate

Compound 4 (5 g, 21.2 mmol) and compound 5 (5.6 g, 24.3 mmol) werestirred at 0° C. CH₃SO₃H (50 mL) was added dropwise. Then the mixturewas stirred at RT for 16 h. The reaction mixture was poured into crushice, extracted by DCM. The DCM layer was washed with sat. Na₂HPO₄, driedover Na₂SO₄, filtered, concentrated. The residue was purified by silicagel column (DCM:EtOH=50:1), afforded compound 6 (1.2 g, 18%) as lightyellow solid.

Synthesis of ethyl3-(7-hydroxy-4-methyl-6-(N-methylacetamido)-2-oxo-2H-chromen-3-yl)propanoate

Compound 6 (0.7 g, 2.2 mmol) and pyridine (0.18 g, 2.3 mmol) weredissolved in DCM (10 mL). CH₃COCl (0.2 g, 2.5 mmol) was added dropwiseat 0° C. After that the reaction mixture was stirred at RT for 2 h. Thereaction mixture was diluted with DCM (10 mL), washed with 1N HCl,concentrated. The residue was purified by silica gel column(DCM:EtOH=100:1), afforded compound 7 (0.56 g, 70%) as light yellowsolid. ¹HNMR (CDCl₃, 400 MHz): δ 7.38 (s, 1H, ArH), 7.00 (s, 1H, ArH),4.13 (q, J=7.2 Hz, 2H, CH₂), 3.46 (s, 3H, NCH₃), 2.96 (t, J=7.2 Hz, 2H,CH₂), 2.61 (t, J=7.2 Hz, 2H, CH₂), 2.43 (s, 3H, CH₃), 1.90 (s, 3H, CH₃),1.24 (t, J=7.2 Hz, 3H, CH₃).

Synthesis of ethyl3-(8-formyl-7-hydroxy-4-methyl-6-(N-methylacetamido)-2-oxo-2H-chromen-3-yl)propanoate

Compound 7 (516 mg, 1.48 mmol) and HMTA (832.8 mg, 5.94 mmol) were addedto AcOH (13 mL). The reaction mixture was heated to 120° C. for 5 h. Thereaction mixture was concentrated. The residue was purified by prep-HPLCand prep-TLC successively, afforded Synthesis of ethyl3-(8-formyl-7-hydroxy-4-methyl-6-(N-methylacetamido)-2-oxo-2H-chromen-3-yl)propanoate(65 mg, 11.7%) as yellow solid. MS [ESI, MH⁺]: 376.1. ¹HNMR (CDCl₃, 400MHz): δ 12.42 (s, 1H, OH), 10.63 (s, 1H, CHO), 7.67 (s, 1H, ArH), 4.13(q, J=7.2 Hz, 2H, CH₂), 3.21 (s, 3H, NCH₃), 2.98 (t, J=7.2 Hz, 2H, CH₂),2.63 (t, J=7.2 Hz, 2H, CH₂), 2.46 (s, 3H, CH₃), 1.86 (s, 3H, CH₃), 1.24(t, J=7.2 Hz, 3H, CH₃).

Example 53

Synthesis of7-hydroxy-5-methoxy-3-(2-(2-methoxyethoxyl)ethyl)-4-methyl-2H-chromen-2-one

Compound 1 (0.67 g, 4.8 mmol) and compound 2 (1.13 g, 4.8 mmol) werestirred at 0° C. H₃PO₄ (15 mL) was added dropwise. Then the mixture wasstirred at RT for 16 h. The reaction mixture was poured into crush ice,extracted by EA. The EA layer was concentrated; DCM (15 mL) was added,stirred for 15 min. The undissolved material was removed by filtration.The filter was concentrated. The residue was purified by prep-TLC,afforded crude compound 3 (687 mg, 60% purity) without furtherpurification.

Synthesis of7-hydroxy-5-methoxy-3-(2-(2-methoxyethoxyl)ethyl)-4-methyl-2-oxo-2H-chromene-8-carbaldehyde

Compound 3 (0.58 g, 1.88 mmol) and HMTA (1.05 g, 7.5 mmol) were added toAcOH (25 mL). The reaction mixture was heated to 100° C. under N₂ for 3h. The solvent was removed under vacuum, diluted with H₂O, extracted byEA, concentrated. The residue was purified by prep-TLC, afforded7-hydroxy-5-methoxy-3-(2-(2-methoxyethoxyl)ethyl)-4-methyl-2-oxo-2H-chromene-8-carbaldehyde(60 mg, 15.8%) as yellow solid. ¹HNMR (CDCl₃, 400 MHz): δ 12.58 (s, 1H,OH), 10.38 (s, 1H, CHO), 6.26 (s, 1H, ArH), 3.93 (s, 3H, ArOCH₃)3.63-3.60 (m, 4H), 3.53-3.50 (m, 2H), 3.36 (s, 3H, CH₃), 2.95 (t, J=7.2Hz, 2H), 2.56 (s, 3H, CH₃). MS [ESI, MH⁺]: 337.0

Example 54

Synthesis of Compound 2

The solution of NaOH (2.38 g, 0.0595 mol) in H₂O (125 mL) was mixedtogether with the solution of compound 1 (5 g, 0.042 mol) in THF (200mL). Then the mixture was cooled to 0° C., a solution of TsCl (7.38 g,0.0388 mol) in THF (200 mL) was added dropwise while keeping the innertemperature below 5° C. After that, the reaction mixture was stirred at0° C.˜5° C. while monitoring the reaction progress with TLC. After thereaction was completed (˜2 h), the mixture was poured into ice-water(500 mL), extracted with DCM (150 mL×3). The combined DCM was washedwith water and brine, dried over Na₂SO₄, concentrated to afford compound2 (9.50 g, yield: 89%) as light yellow needle solid without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J=8.4 Hz, 2H, ArH),7.33 (d, J=8.4 Hz, 2H, ArH), 4.16 (t, J=4.8 Hz, 2H, CH₂), 3.68 (t, J=4.8Hz, 2H, CH₂), 3.58-3.56 (m, 2H, CH₂), 3.48-3.47 (m, 2H, CH₂), 3.34 (s,3H, OCH₃), 2.44 (s, 3H, ArCH₃).

Synthesis of Compound 3

To the suspension of NaH (0.992 g, 0.0248 mol) in DME (25 mL) was addeddropwise the solution of CH₃COCH₂COOEt (3.07 g, 0.0236 mol) in DME (550mL) at 0° C. After that, the mixture was stirred at RT for 30 min. Thesolution of compound 2 (6.79 g, 0.0247 mmol) in DME (100 mL) and NaI(3.72 g, 0.0248 mol) were added to the reaction mixture successively atRT. The result mixture was stirred at RT for 2h until some precipitatewas formed. Then the mixture was heated to 80° C. overnight under N₂.Progress of this reaction was monitored by LCMS. After the reaction wascompleted (˜16 h), the undisclosed material was removed by filtration.The filtrate was concentrated, diluted by H₂O, acidified by 2N HCl topH=˜3, extracted by DCM (100 mL×3). The combined DCM was concentrated,purified by silica gel column (PE:EA=6:1) to afford compound 3 as lightyellow oil (1.8 g, 32% yield). HNMR indicated few EA entrained thatdidn't make influence on the next step.

¹H NMR (400 MHz, CDCl₃): δ 4.19-4.16 (m, 2H, CH₂), 4.12-4.10 (m, 1H,CH), 3.66 (m, 1H, CH), 3.52-3.48 (m, 6H, 3CH₂), 3.36 (s, 3H, OCH₃), 2.25(s, 3H, COCH₃), 2.17-2.11 (m, 2H, CH₂), 1.49 (t, J=7.2 Hz, 3H, CH₃).

Synthesis of Compound 5

Compound 3 (2.25 g, 0.0097 mol) and 2-hydroxyl-3-methoxyl-phenol (1.30g, 0.0093 mol) were added to H₃PO₄ (200 mL). The reaction mixture wasstirred at 45° C. for 2 days. Progress of this reaction was monitored byLCMS. After the reaction was completed (˜48 h), the mixture was dilutedwith EA (100 mL), poured into ice-water (1 L) and stirred for 15 min.Then the solid was collected by filtration, washed with cold sat NaHCO₃,brine and H₂O successively. The solid was dried by azeotropy withtoluene to afford compound 4 as light yellow solid (1.25 g, 41% yield).¹H NMR (400 MHz, DMSO-d6): δ 7.14 (s, 1H, ArH), 6.74 (s, 1H, ArH), 3.85(s, 3H, CH₃), 3.49-3.47 (m, 4H, 2CH₂), 3.41-3.33 (m, 2H, CH₂), 3.20 (s,3H, CH₃), 2.78 (t, J=7.2 Hz, 2H, CH₂), 2.40 (s, 3H, CH₃).

7-Hydroxy-6-methoxy-3-(2-(2-methoxyethoxyl)ethyl)-4-methyl-2-oxo-2H-chromene-8-carbaldehyde

Compound 5 (2.0 g, 0.0064 mol) and HMTA (3.65 g, 0.026 mol) were addedto TFA (85 mL). The reaction mixture was heated to 95° C. for 2h.Progress of this reaction was monitored by LCMS. After the reaction wascompleted, the reaction mixture was concentrated. The residue wasdiluted with H₂O, extracted by DCM (100 mL×3), the combined DCM waswashed with cold sat. NaHCO₃, brine, dried over Na₂SO₄, concentrated.The crude product was purified by silica gel column (DCM: MeOH=100:1) toafforded 1.3 g of desired product (94.7% purity on 220 nm). The productwas further purification by recrystallization from EA to afford7-hydroxy-6-methoxy-3-(2-(2-methoxyethoxyl)ethyl)-4-methyl-2-oxo-2H-chromene-8-carbaldehyde(0.8 g, 37% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 12.46 (s,1H, OH), 10.66 (s, 1H, CHO), 7.30 (s, 1H, ArH), 4.01 (s, 3H, ArOCH₃),3.72 (t, J=6.8 Hz, 2H, CH₂), 3.65-3.64 (m, 2H, CH₂), 3.56-3.55 (m, 2H,CH₂), 3.40 (s, 3H, OCH₃), 3.02 (t, J=6.8 Hz, 2H, CH₂), 2.49 (s, 3H,CH₃); LCMS [M+H]⁺=337.2.

Example 55

7-Hydroxy-4-methyl-3-[3-(4-methyl-piperazin-1-yl)-3-oxo-propenyl]-2-oxo-2H-chromene-8-carbaldehyde

3-Bromo-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (142 mg,0.50 mmol), 1-(4-methyl-piperazin-1-yl)-propenone (93 mg, 0.60 mmol),palladium acetate (4 mg, 15 μmol), tri-o-tolyl-phosphane (9 mg, 30 μmol)and silver acetate (167 mg, 1.0 mmol) were dissolved in abs.N,N-dimethylformamide (4 mL). The mixture was irradiated in a microwavereactor for 1 h at 120° C. under inert atmosphere. The reaction mixturewas poured into water (10 mL) and extracted with chloroform (3×15 mL).The combined organic layers were dried (Na2SO4) and evaporated. Thetitle compound (15 mg, 0.042 mmol, 8%) was isolated by columnchromatography (Kieselgel 60), with chloroform as eluent, as a yellowpowder. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (s, 1H), 8.05 (d, J=9.0Hz, 1H), 7.59 (d, J=15.1 Hz, 1H), 7.50 (d, J=15.1 Hz, 1H), 6.92 (d,J=9.0 Hz, 1H), 3.56-3.66 (m, 4H), 2.55 (s, 3H), 2.38 (br. s., 4H), 2.27(s, 3H).

Example 56

Synthesis of Compound 2

To the mixture of compound 1 (3.0 g, 21.0 mmol) and compound 2 (4.0 g,25.0 mmol), H₂SO₄ (9 mL) was added slowly at 0° C. The mixture wasstirred at RT overnight. The reaction mixture was poured into H₂O (10mL) and stirred for 30 mins, the formed precipitate was filtered andwashed with water, dried to give compound 3 (2.0 g, 41% yield) as lightyellow solid.

Synthesis of Compound7-hydroxy-4-isopropyl-6-methoxy-2-oxo-2H-chromene-8-carbaldehyde

A mixture of compound 3 (500 mg, 2.1 mmol) and HMTA (1.1 g, 9.4 mmol) inTFA (50 mL) was heated to 90° C. under N₂ for 2 h. LC-MS indicated thatthe reaction was completed. After cooling to RT, the solvent was removedunder vacuum. The residue was purified by prep-HPLC, afforded7-hydroxy-4-isopropyl-6-methoxy-2-oxo-2H-chromene-8-carbaldehyde (150mg, 26%). ¹HNMR (DMSO, 400 MHz): δ 11.91 (s, 1H, OH), 10.42 (s, 1H,CHO), 7.50 (s, 1H, ArH), 6.23 (s, 1H, ArH), 3.90 (s, 3H, CH₃), 3.29 (s,1H, CH), 1.24 (d, 6H, J=6.8 Hz, 2CH₃). MS [ESI, MH⁺]: 263.1.

Example 57

Synthesis of Compound 3

A suspension of compound 2 (11 g, 105 mmol) and compound 1 (2 g, 6.8mmol) was heated to 120° C. for 16 h. The reaction mixture was dilutedwith DCM (300 mL), washed with 1 N aq. HCl (20 mL×3), sat. NaHCO₃ (50mL), brine (50 mL), dried over MgSO₄ and concentrated to give theresidue, then recrystallized in MeOH to give compound 6 (1.5 g, 63.0%)as white solid.

2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-(methoxymethoxy)ethyl)acetamide

A solution of compound 3 (750 mg, 1.98 mmol) and HMTA (1.11 g, 7.92mmol) in AcOH (50 mL) was heated to 100° C. for 2 h. After cooling toRT, the reaction mixture was concentrated to give the residue, and thendiluted with DCM (200 mL), washed with water (20 mL), brine (20 mL),dried over Na₂SO₄ concentrated to give2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-(methoxymethoxy)ethyl)acetamide(200 mg, 26.7%). ¹H NMR: (DMSO, 400 MHz) δ 11.78 (s, 1H, OH), 10.41 (s,1H, CHO), 7.88 (s, 1H, ArH), 7.45 (br, 1H, NH), 3.90 (s, 3H, OCH₃), 3.46(s, 2H, CH₂), 3.37-3.33 (m, 2H, CH₂), 3.08 (d, J=6.0, 2H, CH₂), 2.36 (s,3H, CH₃); MS [ESI, MH⁺]: 336.2.

2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-hydroxyethyl)acetamide

A solution of2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-(methoxymethoxy)ethyl)acetamide(400 mg, 1.06 mmol) in CHCl₃ (40 mL) and conc. HCl (20 mL) was heated toreflux for 1 h, and then concentrated to give the residue and purifiedby prep. HPLC to give2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-hydroxyethyl)acetamide(40 mg, 11.3%) as yellow solid. ¹H NMR: (CDCl₃, 400 MHz) δ 12.47 (d,J=0.4 Hz, 1H, OH), 10.02 (s, 1H, CHO), 7.22 (s, 1H, ArH), 6.60 (br, 1H,NH), 4.63 (s, 2H, CH₂), 3.97 (s, 3H, OCH₃), 3.60 (t, J=5.4 Hz, 4H, CH₂),3.45 (m, 2H, CH₂), 3.36 (d, J=0.4 Hz, 2H, CH₂), 2.57 (s, 3H, CH₃); MS[ESI, MH⁺]: 380.2.

Example 58

Synthesis of Compound 3

To a suspension of compound 1 (30 g, 0.209 mol) and compound 2 (41 g,0.313 mol) was added CH₃SO₃H (200 mL) while keeping inner temperaturebelow 25° C. The reaction mixture was stirred at RT for 16 h and thenpoured in to ice water, filtered and the filter cake was washed withwater (50 mL×3), dried in vacuum to give compound 3 (30 g, 68%) as whitesolid.

Synthesis of Compound 4

To a suspension of compound 3 (30 g, 0.143 mol) in AcOH (300 mL) wasadded Br₂ (22.7 g, 0.143 mol) dropwise at 60° C. for 30 min. Aftercooling to RT, the reaction mixture was filtered and the filter cake waswashed with water (50 mL×4), dried in vacuum to give compound 4 (30 g,73%) as white solid.

Synthesis of Compound 5

A suspension of compound 4 (30 g, 0.104 mol) in Ac₂O (200 mL) was heatedto 130° C. for 2 h. After cooling to room temperature, the reactionmixture was filtered and the filter cake was washed with water (50mL×3), dried in vacuum to give compound 5 as white solid (28 g, 81.1%).

Synthesis of Compound 7

A suspension of compound 5 (1 g, 3.0 mmol), compound 6 (1.41 g, 6.0mmol), Pd (dppf) ₂Cl₂ (110 mg, 0.15 mmol) and Na₂CO₃ (0.636 g, 6.0 mmol)in DMF (50 mL) and water (5 mL) was heated to 100° C. for 10 h. Thesolvent was removed under reduced pressure and then purified by columnchromatography on silica gel to give compound 7 (600 mg, 50%) as yellowsolid.

Synthesis of Compound 9

A solution of compound 7 (1 eq) and HMTA (4 eq) in TFA was heated to 70°C. for 16 h. After cooling to room temperature, the reaction mixture wasconcentrated to give the residue, and then purified by prep. HPLC togive compound 9.

4-(6-Chloro-8-formyl-7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)benzamidewas obtained by the above procedure from amine A1 7.0% yield ¹H NMR(CDCl₃ 400 MHz): δ 12.74 (s, 1H, OH), 10.65 (s, 1H, CHO), 7.89 (d, J=8Hz, 3H, ArH), 7.38 (d, J=8.8 Hz, 2H, ArH), 6.55 (br, 1H, NH), 3.68 (t,J=7.2 Hz, 2H, CH₂), 3.58 (t, J=7.2 Hz, 2H, CH₂), 3.40 (s, 3H, OCH₃),2.30 (s, 3H, CH₃); MS [ESI, MH⁺]: 416.2.

6-Chloro-7-hydroxy-4-methyl-3-(4-(morpholine-4-carbonyl)phenyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 9.4% yield ¹H NMR:(CDCl₃ 400 MHz) δ 12.7 (s, 1H, OH), 10.66 (s, 1H, CHO), 7.90 (s, 1H,ArH), 7.53 (t, J=8 Hz, 2H, ArH), 7.37 (t, J=12 Hz, 2H, ArH) 3.77-3.55(m, 8H), 2.30 (s, 3H, CH₃); MS [ESI, MH⁺]: 428.2

4-(6-Chloro-8-formyl-7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)benzamidewas obtained by the above procedure from amine A5 9.5% yield ¹H NMR(DMSO 400 MHz) δ 10.46 (s, 1H, CHO), 8.78 (br, 1H. NH), 8.23 (s, 1H,ArH), 7.94 (d, J=8.4 Hz, 2H, ArH), 7.45 (d, J=8.4 Hz 2H, ArH) 3.82 (s,4H, 2CH₂), 3.65 (d, J=4.0 Hz, 2H, CH₂), 2.53 (d, J=4.0 Hz 2H, CH₂), 2.26(s, 3H, CH₃). MS [ESI, MH⁺]: 471.3.

To a suspension of compound 8 1.0 eq) and DMF (5 mL) in DCM (1 L) wasadded (COCl)₂ (2 eq) dropwise at 0° C. in 1 h. The reaction mixture wasstirred at room temperature overnight and then removed the solvent togive the chloride acid. To a solution of the chloride acid in DCM (1 L)was added morpholine (1.0 eq) and TEA (2.0 eq) dropwise at 0° C. After 2h, the solvent was removed to give compound 6.

Example 59

Synthesis of Compound 2

To a solution of compound 1 (50 g, 0.4 mol) and 2-Methoxy-ethanol (200mL) in dioxane (800 mL) and MeOH (200 mL) was bubbled HCl gas at 0° C.over 20 min, and then heated to 90° C. for 16 h. The reaction mixturewas concentrated under reduced pressure to removed dioxane, and then theresidue was purified by column chromatography on silica gel to givecompound 2 (30 g, 40.8%) as waxy solid.

MS [ESI, MH⁺]: 185.2

Synthesis of Compound 4

To a mixture of compound 2 (15.5 g, 0.084 mol) and compound 2 (23.5 g,0.101 mol) was added H₃PO₄ (100 mL) dropwise at 0° C. over 30 min, andthen warmed to RT for 16 h. The reaction mixture was poured into icewater and the precipitate was filtered and recrystallized from EtOAc togive compound 4 as (9.5 g, 32.3%) white solid.

Synthesis of Compound 5

A mixture of compound 4 1 eq) and amine was heated to 120° C. for 16 h.The reaction mixture was concentrated to give the residue, and thenpurified by column chromatography on silica gel to give the crudeproduct, and then recrystallized from MeOH to give compound 5

Synthesis of Compound 6

A solution of compound 5 (1 eq) and HMTA (4.0 eq) in TFA was heated to100° C. for 3 h. After cooling to room temperature, the reaction mixturewas concentrated to give the residue, and then purified by Prep-HPLC togive compound 6

3-(8-Formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 15% yield. ¹H NMR(CDCl₃, 400 MHz): δ 12.58 (s, 1H, OH), 10.40 (d, J=2.8 Hz, CHO), 6.25(d, J=2.4, 1H, ArH), 6.04 (br, 1H, NH), 4.21 (d, J=2.4 Hz, ArOCH₂), 3.79(d, J=2.8 Hz, OCH₂), 3.44 (s, 7H), 3.33 (s, 3H, OCH₃), 2.97 (s, 2H,CH₂), 2.64 (s, 3H, CH₃), 2.44 (s, 2H, CH₂); MS [ESI, MH⁺]: 408.3.

7-Hydroxy-5-(2-methoxyethoxy)-4-methyl-3-(3-morpholino-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 52.2% yield ¹H NMR(CDCl₃ 400 MHz): δ 12.55 (d, J=3.2 Hz, OH), 10.37 (d, J=3.2 Hz, 1H,CHO), 6.23 (d, J=3.2 Hz, 1H, ArH), 4.20 (t, J=3.0 Hz, 2H, ArOCH₂),3.81-3.79 (m, 2H, OCH₂), 3.66 (s, 4H, 2CH₂), 3.62 (s, 2H, CH₂), 3.54 (s,2H, CH₂), 3.43 (d, J=3.6 Hz, 3H, OCH₃), 2.96-2.92 (m, 2H, CH₂), 2.63 (d,J=3.2 Hz, 3H, CH₃), 2.56-2.51 (m, 2H, CH₂). MS [ESI, MH⁺]: 420.2.

7-Hydroxy-5-(2-methoxyethoxy)-4-methyl-3-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3. 28% yield. ¹H NMR(D₂O, 400 MHz): δ 9.69 (s, 1H, CHO), 6.01 (s, 1H, ArH), 4.42 (s, 1H,CH₂), 4.12 (s, 1H, CH₂), 3.98 (s, 1H, ArOCH₂), 3.72 (s, 2H, OCH₂),3.50-3.32 (m, 3H, CH₂), 3.31 (s, 3H, OCH₃), 3.07-2.93 (m, 3H, CH₂), 2.81(s, 3H, NCH₃), 2.57 (d, J=7.6 Hz, 2H, CH₂), 2.45 (t, J=7.4 Hz, 2H, CH₂),2.23 (s, 3H, CH₃); MS [ESI, MH⁺]: 433.2.

N-Ethyl-3-(8-formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A4. 9.3% yield. ¹H NMR(CDCl₃ 400 MHz): δ 12.59 (s, 1H, OH), 10.40 (s, 1H, CHO), 6.26 (s, 1H,ArH), 5.71 (s, 1H, CONH), 4.23-4.21 (m, 2H, ArOCH₂), 3.82-3.79 (m, 2H,OCH₂), 3.45 (d, J=2.4 Hz, 3H, OCH₃), 3.29 (t, J=5.6 Hz, 2H, CH₂), 2.98(t, J=7.4 Hz, 2H, CH₂), 2.65 (s, 3H, CH₃), 2.41 (t, J=7.6 Hz, 2H, CH₂),1.15-1.12 (m, 3H, CH₃). MS [ESI, MH⁺]: 378.1

3-(8-Formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A5. 23% yield. ¹H NMR(D₂O, 400 MHz): δ 9.74 (s, 1H, CHO), 6.06 (s, 1H, ArH), 4.01 (s, 2H,ArOCH₂), 3.97 (s, 2H, OCH₂), 3.75-3.69 (m, 4H, CH₂), 3.49 (s, 4H, CH₂),3.32 (s, 3H, OCH₃), 3.19 (t, J=6.0 Hz, CH₂), 3.12-3.08 (m, 2H, CH₂),2.63 (d, J=8.4 Hz, 2H, CH₂), 2.26 (s, 3H, CH₃); MS [ESI, MH⁺]: 463.2.

N-(2-(Dimethylamino)ethyl)-3-(8-formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A6. 9.5% yield ¹H NMR(D₂O 400 MHz): δ 9.95 (s, 1H, CHO), 6.25 (s, 1H, ArH), 4.20 (s, 2H,ArOCH₂), 3.91 (s, 2H, OCH₂), 3.59 (t, J=6.0 Hz, 2H, CH₂), 3.48 (s, 3H,OCH₃), 3.32 (t, J=6.0 Hz, 2H, CH₂), 2.95 (s, 6H, 2NCH₃), 2.81 (t, J=7.8Hz, 2H), 2.45 (s, 5H); MS [ESI, MH⁺]: 421.2

Example 60

Synthesis of Compound 3

To a mixture of compound 1 (15.5 g, 0.084 mol) and compound 2 (21.8 g,0.101 mol) was added H₃PO₄ (100 mL) dropwise at 0° C. over 30 min, andthen warmed to RT for 16 h. The reaction mixture was poured into icewater and the precipitate was filtered and recrystallized from EtOAc togive compound 3 (5.5 g, 19.5%) as white solid.

MS [ESI, MH⁺]: 337.1

Synthesis of Compound 4

A mixture of compound 4 (2.0 g, 6.0 mmol) and amine (20 mL) was heatedto 120° C. for 16 h. The reaction mixture was concentrated to give theresidue, and then purified by column chromatography on silica gel togive the crude product, and then recrystallized in MeCN to give compound5 (0.4 g, 18.4%) as white solid.

Synthesis of Compound 5

A solution of compound 4 (1 eq) and HMTA (4.0 eq) in AcOH was heated to100° C. for 3 h. After cooling to room temperature, the reaction mixturewas concentrated to give the residue, and then purified by Prep-HPLC togive compound 5

2-(8-Formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)acetamidewas obtained by the above procedure from amine A1. 3.5% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.61 (s, 1H, OH), 10.40 (s, 1H, CHO), 6.43 (br, 1H,NH), 6.27 (s, 1H, ArH), 4.22 (t, J=4.4 Hz, 2H, ArOCH₂), 3.79 (t, J=4.4Hz, 2H, OCH₂), 3.58 (s, 3H, CH₂), 3.43 (m, 7H), 3.35 (d, J=4.0 Hz, 3H,OCH₃), 2.72 (s, 3H, CH₃). MS [ESI, MH⁺]: 394.1

7-Hydroxy-5-(2-methoxyethoxy)-4-methyl-3-(2-morpholino-2-oxoethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 14% yield. ¹H NMR(CDCl₃, 400 MHz): δ 12.62 (s, 1H, OH), 10.41 (s, 1H, CHO), 6.27 (s, 1H,ArH), 4.22 (t, J=4.4 Hz, 2H, ArOCH₂), 3.81-3.76 (m, 4H, OCH₂ and CH₂),3.70 (d, J=3.6 Hz, 6H, CH₂), 3.65 (d, J=4.8 Hz, 2H, CH₂), 3.43 (s, 3H,OCH₃), 2.61 (s, 3H, CH₃) MS [ESI, MH⁺]: 406.1

7-Hydroxy-5-(2-methoxyethoxy)-4-methyl-3-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3. 3.9% yield. ¹H NMR(D₂O, 400 MHz): δ 9.89 (s, 1H, CHO), 6.18 (s, 1H, ArH), 4.60 (d, J=12.4Hz, 1H), 4.41 (d, J=14.8 Hz, 1H), 4.14 (s, 2H, ArOCH₂), 3.88-3.62 (m,8H), 3.45 (s, 3H, OCH₃), 3.33 (d, J=2.8 Hz, 1H), 3.19 (d, J=12.8 Hz, 2H,CH₂), 3.01 (s, 3H, NCH₃), 2.37 (s, 3H, CH₃); MS [ESI, MH⁺]: 419.3.

N-Ethyl-2-(8-formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A4. 9.6% yield. ¹HNMR(MeOD, 400 MHz): δ 10.35 (s, 1H, CHO), 6.46 (s, 1H, ArH), 4.30-4.28 (m,2H, ArOCH₂), 3.82-3.80 (m, 2H, OCH₂), 3.59 (s, 2H, CH₂), 3.41 (s, 3H,OCH₃), 3.22-3.20 (m, 2H, CH₂), 2.59 (s, 3H, CH₃), 1.12 (t, J=4.0 Hz, 3H,CH₃). MS [ESI, MH⁺]: 364.1

2-(8-Formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)acetamidewas obtained by the above procedure from amine A5. 5.0% yield. ¹H NMR(CDCl₃, 400 MHz): δ 10.40 (s, 1H, CHO), 6.83 (br, 1H, NH), 6.27 (s, 1H,ArH), 4.22 (t, J=4.4 Hz, 2H, ArOCH₂), 3.79 (t, J=4.4 Hz, 2H, OCH₂), 3.74(s, 4H, CH₂), 3.63 (s, 2H, CH₂), 3.43 (s, 3H, OCH₃), 3.38 (d, J=5.2 Hz,2H, CH₂), 2.71 (s, 3H, CH₃), 2.56 (s, 6H, CH₂). MS [ESI, MH⁺]:449.1

N-(2-(Dimethylamino)ethyl)-2-(8-formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A6. 10% yield. ¹HNMR(D₂O, 400 MHz): δ 10.12 (s, 1H, CHO), 6.40 (s, 1H, ArH), 4.29 (d, J=4.0Hz, 2H, ArOCH₂), 3.96 (t, J=2.0 Hz, 2H, OCH₂), 3.70-3.65 (m, 4H, 2CH₂),3.50 (s, 3H, OCH₃), 3.36 (t, J=6.2 Hz, 2H, CH₂) 2.97 (s, 6H, 2NCH₃),2.54 (s, 3H, CH₃). MS [ESI, MH⁺]: 407.1

Ethyl2-(8-formyl-7-hydroxy-5-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)acetate

¹HNMR (CDCl₃, 400 MHz): δ 12.62 (s, 1H, OH), 10.41 (s, 1H, CHO), 6.27(s, 1H, ArH), 4.23-4.18 (m, 4H), 3.80 (t, J=4.6 Hz, 2H, OCH₂), 3.72 (s,2H, CH₂), 3.44 (s, 3H, OCH₃), 2.56 (s, 3H, CH₃), 1.27 (t, J=4.0 Hz, 3H,CH₃); MS [ESI, MH⁺]: 365.2.

Example 61

Synthesis of Compound 3

To a mixture of compound 1 (1.0 g, 5.43 mmol) and compound 2 (0.94 g,6.52 mmol) was added MeSO₃H (20 mL) dropwise at 0° C. over 30 min, andthen warmed to RT for 16 h. The reaction mixture was poured into icewater and the precipitate was filtered and recrystallized from EtOAc togive compound 3 (830 mg, 55.8%) as white solid.

7-Hydroxy-5-(2-methoxyethoxy)-3,4-dimethyl-2-oxo-2H-chromene-8-carbaldehyde

A solution of compound 3 (800 mg, 3.14 mmol) and HMTA (1.76 g, 12.6mmol) in AcOH (50 mL) was heated to 100° C. for 2 h. After cooling toroom temperature, the reaction mixture was concentrated to give theresidue, and then purified by Prep-HPLC to give the target compound (32mg, 3.5%). ¹H NMR (CDCl₃, 400 MHz): δ 12.57 (s, 1H, OH), 10.41 (s, 1H,CHO), 6.24 (s, 1H, ArH), 4.23-4.21 (m, 2H, Ar OCH₂), 3.82-3.80 (m, 2H,OCH₂), 3.44 (s, 3H, OCH₃), 2.57 (d, J=0.8 Hz, 3H, CH₃), 2.17 (d, J=0.8Hz 3H, CH₃). LC-MS MS [ESI, MH⁺]: 293.0.

Example 62

Synthesis of Compound 1

To a solution of compound a (300 g, 1.98 mol) and SeO₂ (17.4 g, 0.156mol) in DCM (4 L) was added H₂O₂ (512 mL) dropwise at ice-bath. Themixture solution was stirred at RT for 16 h. The reaction mixture turnedto dark-brown in the period. The reaction was monitored by TLC(PE:EA=1:1). After the material was consumed completely (˜12 h), theorganic phase was separated and washed with 10% NaHSO₃ (1 L), followedby Na₂CO₃ (1 L) and brine (1 L), then dried on NaSO4, the solvent wasremoved to get the crude compound 2 and use at the next step directly.

The crude compound b was hydrolyzed in a mixture of MeOH (3 L) and 10%KOH (2 L) at RT over night. After MeOH was removed, the mixture wasacidified by 6M HCl to PH=3 and extracted with DCM (2 L×8). The combinedorganic phase was washed with brine and dried on NaSO₄. After thesolvent was removed, the residue was purified by chromatography(EA:PE=6:1 to EA:PE=4:1) to give compound 3 (140 g, 50.5%) aslight-yellow solid. ¹HNMR (MeOD, 400 MHz): δ 6.70 (d, J=8.8 Hz, 1H,ArH), 6.29 (d, J=3.2 Hz, 1H, ArH), 6.18 (dd, J=8.8, 2.8 Hz, 1H, ArH),3.73 (s, 3H, CH₃).

Synthesis of Compound 3

To a suspension of compound 1 (120 g, 0.86 mol) in diethylacetylsuccinate (220 g, 1.03 mol), CH₃SO₃H (1200 mL) was added in oneportion. The mixture was stirred at RT overnight. LC-MS showed thatstarting material was consumed completely. The reaction mixture waspoured into ice-water (1000 ml) and stirred for 30 min. The formedprecipitate was filtered and washed with water and EA, dried to affordthe crude product (150 g, 60%) as white solid. ¹HNMR (MeOD, 400 MHz): δ7.15 (s, 1H, ArH), 6.75 (s, 1H, ArH), 4.18-4.12 (q, 2H, CH2), 3.93 (s,3H, CH₃), 2.41 (s, 3H, CH₃), 1.25 (t, 3H, CH₃).

Synthesis of Compound 4

Compound 3 (180 g, 0.6 mol) was added into 4M NaOH (500 mL) in oneportion and stirred at RT overnight. TLC (EA/MeOH=10/1) indicated thatthe reaction was complete. The reaction mixture was acidified with 5MHCl to PH=3. The formed precipitate was filtered, which was washed withEA and dried in vacuo to give compound 4 as white solid (140 g, 67%)

Synthesis of Compound 5a

To a suspension of compound 4 (1 eq) in DMF, amine and PyBOP (1.2 eq)was added sequentially. The mixture was cooled to 0° C., DIPEA (1.2 eq)was then added dropwise while controlling the temperature below 10° C.The reaction mixture was stirred at RT overnight. LCMS showed thatstarting material was consumed completed, the precipitate was filteredand washed with water and EA, dried in vacuo to give compound 5a as awhite solid. 5A2, 5A3 used the method

Synthesis of Compound 5b

Compound 3 (1.0 eq) was added to amine. The reaction mixture was stirredat 120° C. for 48 h. LC-MS showed that the starting material was almostconsumed completely. The solvent was removed under vacuum. The residuewas washed with DCM (3×5 mL) and concentrated under vacuum, affordedcompound 5b, 5A1, 5A4, 5A5 used the method

Synthesis of Compound 6

A mixture of compound 5 (1 eq) and HMTA (4 eq) in HOAc was heated at120° C. under nitrogen for 1.5 h. The reaction mixture turned todark-yellow in the period. LCMS indicated that the reaction wascompleted. After cooled to RT, the solvent was removed under reducedpressure, the product was purified by Prep-HPLC to give compound 6.

2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)acetamidewas obtained by the above procedure from amine A1.18% yield

¹HNMR (CDCl₃, 400 MHz): δ 12.48 (s, 1H, OH), 10.61 (s, 1H, CHO), 7.22(s, 1H, ArH), 6.61 (br, 1H, NH), 3.97 (s, 3H, OCH₃), 3.61 (s, 2H, CH₂),3.46-341 (m, 4H, 2CH₂), 3.36 (s, 3H, CH₃), 2.55 (s, 3H, CH₃), MS [ESI,MH⁺]: 350.1

7-Hydroxy-6-methoxy-4-methyl-3-(2-morpholino-2-oxoethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2.46% yield

¹H NMR (CDCl₃, 400 MHz): δ 12.45 (s, 1H, OH), 10.59 (s, 1H, CHO), 7.24(s, 1H, ArH), 3.95 (s, 3H, OCH₃), 3.78-3.62 (m, 10H) 2.46 (s, 3H, CH₃).MS [ESI, MH⁺]: 362.2.

7-Hydroxy-6-methoxy-4-methyl-3-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3.7.7% yield. ¹HNMR(D₂O, 400 MHz) δ 10.10 (s, 1H, CHO), 7.11 (s, 1H, ArH), 4.44 (d, 1H,J=12.0 HZ, CH), 4.29 (d, 1H, J=14.4 HZ, CH), 3.74-2.98 (m, 11H), 2.85(s, 3H₂OCH₃), 2.19 (s, 3H, CH₃); MS [ESI, MH⁺]: 375.1.

N-Ethyl-2-(8-formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A4.18% yield. ¹HNMR(CDCl3, 400 MHz) δ 12.49 (s, 1H, OH), 10.61 (s, 1H, CHO), 7.22 (s, 1H,ArH), 6.48 (br, 1H, NH), 3.97 (s, 3H₂OCH₃), 3.60 (s, 2H, CH₂), 3.28-3.23(m, 2H, CH₂), 2.57 (s, 3H, CH₃), 1.13 (t, 3H, J=7.2 HZ, CH3); MS [ESI,MH⁺]: 320.2.

N-(2-(dimethylamino)ethyl)-2-(8-formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A6.9.2% yield. ¹HNMR(D2O, 400 MHz): 10.61 (s, 1H, CHO), 7.26 (s, 1H, ArH), 3.90 (s, 3H,OCH₃), 3.69-3.64 (m, 4H, 2CH₂), 3.56 (t, 2H, J=6.0 HZ, CH₂), 2.95 (s,6H, 2NCH₃), 2.39 (s, 3H, CH₃); MS [ESI, MH⁺]: 363.3.

Example 63

Synthesis of Compound 3

To a suspension of compound 1 (8.8 g, 0.063 mol) in compound 2 (18 g,0.078 mol), CH₃SO₃H (144 mL) was added in one portion. The mixture wasstirred at RT for 12 h. LC-MS showed that starting material was consumedcompletely. The reaction mixture was poured into ice-water (300 mL) andstirred for 30 min. The formed precipitate was filtered and washed withwater and EA, dried to afford the crude Compound 3 (11.2 g, 59%) aswhite solid; MS [ESI, MH⁺]: 306.9.

Synthesis of Compound 4

Compound 3 (1.0 eq) was added to amine, The reaction mixture was stirredat 120° C. for 48 h. LC-MS showed that the starting material was almostconsumed completely. The solvent was removed under vacuum. The residuewas washed with DCM and concentrated under vacuum to afforded compound4.

Synthesis of Compound 5

A mixture of compound 4 (1.0 eq) and HMTA (4.0 eq) in TFA was heated to90° C. under nitrogen for 2 h. LC-MS indicated that the reaction wascompleted. After cooled to RT, the solvent was removed under vacuum. Theresidue was purified by Prep-HPLC, afforded compound 5.

3-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 23.5% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.42 (s, 1H, OH), 10.61 (s, 1H, CHO), 7.20 (s, 1H,ArH), 3.41 (m, 4H, 2CH₂), 3.30 (s, 3H, CH₃), 2.99 (t, 2H, J=7.2 Hz,CH₂), 2.52-2.48 (m, 5H); MS [ESI, MH⁺]: 364.2.

7-Hydroxy-6-methoxy-4-methyl-3-(3-morpholino-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 39.6% yield

¹HNMR (MeOD, 400 MHz): δ 7.20 (s, 1H, CHO), 6.01 (s, 1H, ArH), 3.93 (s,3H, OCH₃), 3.63-3.60 (m, 4H, 2CH₂), 3.58-3.55 (m, 4H, 2CH₂), 2.92 (t,2H, J=7.6 Hz, CH₂), 2.61 (t, 2H, J=7.6 Hz, CH₂), 2.48 (s, 3H, CH₃); MS[ESI, MH⁺]: 376.2.

7-Hydroxy-6-methoxy-4-methyl-3-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3.4.6% yield. ¹HNMR(CDCl₃, 400 MHz): δ 10.61 (s, 1H, CHO), 7.21 (s, 1H, ArH), 3.96 (s, 3H,CH₃), 3.60-3.59 (m, 3H, OCH₃), 2.97 (t, 2H, J=7.6. Hz, CH₂), 2.64 (t,2H, J=7.6 Hz, 2H, CH₂), 2.50-2.34 (m, 11H); MS [ESI, MH⁺]: 389.2.

N-Ethyl-3-(8-formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A4. 1.2% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.39 (s, 1H, OH), 10.58 (s, 1H, CHO), 7.20 (s, 1H,ArH), 5.71 (s, 1H, NH), 3.95 (s, 3H, OCH₃), 3.25 (t, 2H, J=5.6 Hz, CH₂),2.98 (t, 2H, J=6.8 Hz, CH₂), 2.47 (s, 5H), 1.11-1.07 (m, 3H, CH₃); MS[ESI, MH⁺]: 334.1

N-(2-(Dimethylamino)ethyl)-3-(8-formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A6.16% yield. ¹HNMR(DMSO-d6, 400 MHz): 10.44 (s, 1H, CHO), 8.24 (s, 1H, OH), 7.46 (s, 1H,ArH), 3.92 (s, 3H, CH₃), 3.41-3.36 (m, 2H, CH₂), 2.83-2.79 (m, 2H, CH₂),2.76-2.74 (m, 6H), 2.49 (s, 3H, CH₃), 2.45-2.30 (m, 2H, CH₂); ¹HNMR(MeOD, 400 MHz): 7.20 (d, 1H, J=12.8 Hz, ArH), 5.99 (s, 1H, CHO), 3.93(s, 3H, CH₃), 3.53-3.50 (m, 2H, CH₂), 3.26-3.23 (m, 2H, CH₂), 2.99-2.96(m, 8H), 2.47 (s, 3H, CH₃), 2.45-2.43 (m, 2H, CH₂).

Example 64

Synthesis of Compound 3

To a solution of compound 1 (1000 g, 7.93 mol) in 1,4-Dixone (2 L) wasadded HCl/MeOH (8 L, saturated with dry HCl at 0° C.) in one portionwith stirring at RT. The result solution was stirred at 80° C.overnight. The reaction was monitored by TLC (PE:EA=1:1) and HPLC. After˜16 h (Note 1), the solvent was removed and the residue was purified bychromatography on silica gel (PE:EA=12:1-8:1) to give compound 2 (514 g,46%) as white solid.

Note 1: HPLC indicated that the material was not consumed. However, thedisubstituted by-product would increase if the reaction was prolonged.

Synthesis of Compound 3

To a suspension of compound 2 (112 g, 0.8 mol) in diethylacetylsuccinate (208 g, 0.96 mol) was added ZnCl₂ (112 g, 0.82 mol) inone portion with stirring at RT. The mixture solution stirred at 100° C.overnight. LC-MS showed that starting material was consumed completely.Then ice-water (400 ml) was added followed by MeOH (1000 ml) and theresult mixture was stirred for 30 mins. The precipitate was filtered andwashed with EA and MeOH (1:1, 800 mL) to afford the desired product (35g, 15%, containing ˜10% isomer) as white solid. MS [ESI, MH⁺]: 293

Synthesis of Compound 4

The compound 3 (100 g, 0.34 mol) was added into 4 N NaOH (256 mL, 1.03mol) in portions with stirring at RT overnight. TLC showed that startingmaterial was consumed completely 5N HCl was added until PH=2. Theprecipitate was filtered and washed with EA, dried in vacuo to givecompound 4 as white solid (60 g, 67%)

Synthesis of Compound 5

To a solution of compound 4 (1 eq) in DMF was added CDI (1.4 eq) in oneportion. The solution was stirred at RT for 3 h. TLC showed thatstarting material was consumed completely. amine (1.4 eq) was added intothe solution in one portion. The mixture solution was stirred at RTovernight. The solvent was removed under reduced pressure and theresidue was treated with EA and DCM to give a suspension. Theprecipitate was filtered to give the product as solid.

Synthesis of Compound 6

A mixture of compound 5 (1 eq) and HMTA (4 eq) in TFA was heated at 90°C. under nitrogen for 1.5h. The reaction mixture turned to dark-yellowin the period. LCMS indicated that the reaction was completed. Aftercooled to RT, the solvent was removed under reduced pressure, theproduct was purified by Prep-HPLC to give compound 6.

2-(8-Formyl-7-hydroxy-5-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)acetamidewas obtained by the above procedure from amine A1. 12% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.56 (s, 1H, OH), 10.34 (s, 1H, CHO), 6.23 (s, 1H,ArH), 3.88 (s, 3H, CH₃), 3.51 (s, 2H, CH₂), 3.37-3.33 (m, 4H, CH₂), 3.28(s, 3H, CH₃), 2.61 (s, 3H, CH₃); MS [ESI, MH⁺]: 350.1

7-Hydroxy-5-methoxy-4-methyl-3-(2-morpholino-2-oxoethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 46% yield.

¹H NMR (CDCl₃, 400 MHz): δ 12.60 (s, 1H, OH), 10.38 (s, 1H, CHO), 6.27(s, 1H, ArH), 3.92 (s, 3H, CH₃), 3.75-3.62 (m, 10H), 2.53 (s, 3H, CH₃).MS [ESI, MH⁺]: 362.2

7-Hydroxy-5-methoxy-4-methyl-3-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3. 9.2% yield. ¹HNMR(D₂O, 400 MHz): δ 9.65 (s, 1H, CHO), 5.99 (s, 1H, ArH), 4.41 (d, 1H,J=12.4 Hz CH₂), 4.22 (d, 1H, J=14.4 Hz, CH₂), 3.65 (s, 3H, CH₃),3.59-3.15 (m, 8H), 2.83 (s, 3H, CH₃), 2.15 (s, 3H, CH₃); MS [ESI, MH⁺]:375.1.

2-(8-Formyl-7-hydroxy-5-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)acetamidewas obtained by the above procedure from amine A6. 9.3% yield. ¹HNMR(D₂O, 400 MHz): δ 9.89 (s, 1H, CHO), 6.23 (s, 1H, ArH), 4.16-3.23 (m,17H), 2.41 (s, 3H, CH₃); MS [ESI, MH⁺]: 405.3

N-(2-(Dimethylamino)ethyl)-2-(8-formyl-7-hydroxy-5-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A5. 11% yield. ¹HNMR(CDCl₃, 400 MHz): δ 10.42 (s, 1H, CHO), 6.75 (br, 1H, NH), 6.31 (s, 1H,ArH), 3.97 (s, 3H, CH₃), 3.61 (s, 2H, CH₂), 3.37 (t, 2H, J=3.2 HZ, CH₂),3.28 (s, 3H, CH₃), 2.52 (t, 2H, J=3.2 HZ, CH₂) 2.33 (s, 6H, 2NCH₃); MS[ESI, MH⁺]: 363.2.

Example 65

Synthesis of Compound 1

A mixture of compound A (200 g, 1.44 mol), BnBr (345 mL, 2.88 mol) andK₂CO₃ (300 g, 2.16 mol) in acetone was refluxed over night. The reactionmixture was filtered and the filtrate was concentrated to give compoundB (421 g, 91.5%). 85% meta-perchlorobenzoic acid (348 g, 1.72 mol) wasadded, with stirring, at ambient temperature to a solution of compound B(421 g, 1.32 mol) in 4000 mL anhydrous methylene chloride. Afterstirring for 30 minutes, the mixture was filtered and the filtrate waswashed with a solution of sodium bicarbonate, then with a solution ofNaHSO₃ and finally with water. After drying on sodium sulphate, thesolvent was evaporated, the residue were taken up in methanol (2000 mL)and water (2000 mL), NaOH (263.8 g, 6.60 mol) was added and stirring wascarried out for 30 minutes after which the mixture was acidified withconcentrated HCl. One extracts with methylene chloride and then washedwith water until neutral. After drying on sodium sulphate, the solventwas evaporated, compound C (300 g, 74%) was obtained. A mixture ofcompound C (22 g, 71.89 mmol), 1-bromo-2-methoxyethane (13.4 mL, 14.38mmol) and K₂CO₃ (30 g, 21.57 mmol) in DMF was stirred at 80° C. overnight. The reaction mixture was filtered and filtrate was concentratedto give compound D (20 g, 84%). A slurry of compound D (20 g, 54.94mmol) and Pd/C (4.0 g) in methanol (500 mL) was stirred at ambienttemperature for 4 hours under 2 atm H₂ (30 PSI). The mixture wasfiltered and filtrate was concentrated, the residue was purified bycolumn chromatogram to give compound 1 (9.7 g, 95%).

Synthesis of Compound 3

Compound 1 (9.7 g, 52.7 mmol) and compound 2 (12.1 g, 52.7 mmol) wereadded to CH₃SO₃H (500 mL) at RT. The mixture was stirred at RT for 12 h.LC-MS showed that starting material was consumed completely. Thereaction mixture was poured into ice-water (300 mL) and stirred for 30min. The formed precipitate was filtered and washed with water and EA,dried, afforded the crude compound 3 (19.5 g, 100%) as white solid.

Synthesis of Compound 4

Compound 3 (1.0 eq) was added to amine The reaction mixture was stirredat 120° C. for 48 h. LC-MS showed that the starting material was almostconsumed completely. The solvent was removed under vacuum. The residuewas washed with DCM and concentrated under vacuum, afforded compound 4.

Synthesis of Compound 5

A mixture of compound 4 (1.0 eq) and HMTA (4.0 eq) in TFA (100 mL) washeated to 90° C. under nitrogen for 2 h. LC-MS indicated that thereaction was completed. After cooled to RT, the solvent was removedunder vacuum. The residue was purified by Prep-HPLC, afforded compound5.

7-Hydroxy-6-(2-methoxyethoxy)-4-methyl-3-(3-morpholino-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 40% yield. ¹HNMR(CDCl₃, 400 MHz) δ 10.56 (s, 1H, CHO), 7.36 (s, 1H, ArH), 4.24-4.21 (m,2H, CH₂), 3.83 (t, J=5.4 Hz, 2H, CH₂), 3.76-3.66 (m, 8H), 3.47 (s, 3H,CH₃), 2.95-2.91 (m, 2H, CH₂), 2.69-2.65 (m, 2H, CH₂), 2.43 (s, 3H, CH₃);MS [ESI, MH⁺]: 420.1.

7-Hydroxy-6-(2-methoxyethoxy)-4-methyl-3-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3. 20% yield. ¹HNMR(D₂O, 400 MHz) δ 10.06 (s, 1H, CHO), 7.12 (s, 1H, ArH), 4.57 (d, J=10.4Hz, 1H), 4.26 (d, J=14.0 Hz, 1H), 4.14 (d, J=0.8 Hz, 2H, CH₂), 3.85 (s,2H, CH₂), 3.67-3.54 (m, 3H), 3.45 (s, 3H, OCH₃), 3.24-3.18 (m, 1H),3.14-3.07 (m, 5H), 2.97-2.94 (m, 2H), 2.76-2.74 (m, 2H), 2.28 (s, 3H,CH₃); MS [ESI, MH⁺]: 433.2.

N-Ethyl-3-(8-formyl-7-hydroxy-6-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A4. 12% yield.

¹HNMR (CDCl₃, 400 MHz) δ 12.36 (s, 1H, OH), 10.58 (s, 1H, CHO) 7.38 (s,1H, ArH), 4.25-4.22 (m, 2H, CH₂), 3.79-3.77 (m, 2H, CH₂), 3.44 (s, 3H,OCH₃), 3.26-3.23 (m, 2H, CH₂), 2.96 (t, J=7.6 Hz, 2H, CH₂), 2.48-2.42(m, 5H), 1.08 (t, J=7.2 Hz, 3H, CH₃); MS [ESI, MH⁺]: 378.1.

3-(8-Formyl-7-hydroxy-6-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 12% yield. ¹HNMR(CDCl₃, 400 MHz) δ 12.41 (d, J=16.8 Hz, 1H, OH), 10.59 (s, 1H, CHO) 7.38(s, 1H, ArH), 4.24 (t, J=4.6 Hz 2H, CH₂), 3.79 (t, J=4.6 Hz, 2H, CH₂),3.45 (s, 3H, OCH₃), 3.41 (d, J=2.4 Hz, 4H, 2CH₂), 3.30 (s, 3H, OCH₃),2.97 (t, J=7.6 Hz, 2H, CH₂), 2.43 (t, J=7.6 Hz, 2H, CH₂), 2.26 (s, 3H,CH₃); MS [ESI, MH⁺]: 408.1.

N-(2-(Dimethylamino)ethyl)-3-(8-formyl-7-hydroxy-6-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A6. 9% yield. ¹HNMR (D₂O,400 MHz) δ 9.66 (s, 1H, CHO), 6.76 (s, 1H, ArH), 3.89 (s, 2H, CH₂), 3.70(s, 2H, CH₂), 3.50 (d, J=5.6 Hz, 2H, CH₂), 3.35 (s, 3H, OCH₃), 3.24 (d,J=5.6 Hz, 2H, CH₂), 2.86 (s, 6H, 2NCH₃), 2.58 (d, J=7.2 Hz, 1H), 2.32(d, J=7.2 Hz, 1H), 2.05 (s, 3H, CH₃); MS [ESI, MH⁺]: 421.2.

3-(8-Formyl-7-hydroxy-6-(2-methoxyethoxy)-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A2. 13% yield. ¹H NMR(D₂O, 400 MHz) δ 9.64 (s, 1H, CHO), 6.75 (s, 1H, ArH), 4.09 (d, J=12.8Hz, 2H, CH₂), 3.88 (s, 2H, CH₂), 3.83 (d, J=13.6 Hz, 2H, CH₂), 3.77 (s,4H, CH₂), 3.70 (s, 2H, CH₂), 3.36 (d, J=2.0 Hz, 3H, OCH₃), 3.30 (d,J=5.6 Hz, 2H, CH₂), 3.15 (t, J=11.6 Hz, 2H, CH₂), 2.58 (s, 2H, CH₂),2.32 (s, 2H, CH₂), 2.05 (s, 3H, CH₃); MS [ESI, MH⁺]: 463.2.

Example 66

Synthesis of Compound 1

The solution of compound (50 g, 396.82 mmol) in solvent(methanol:1,2-dioxane=4:1, 1000 mL) was stirred at 0° C. under HCl (gas)for 1 hour, then the mixture was refluxed for 24 hours. The mixture wasconcentrated and purified by column chromatogram to give Compound 1 (33g, 58.9%).

Synthesis of Compound 3

Compound 1 (25 g, 0.178 mol) and compound 2 (40.7 g, 0.178 mol) wereadded to CH₃SO₃H (500 mL) at RT. The mixture was stirred at RT for 12 h.LC-MS showed that starting material was consumed completely. Thereaction mixture was poured into ice-water (300 mL) and stirred for 30min. The formed precipitate was filtered and washed with water and EA,dried, afforded the crude compound 3 (10.2 g, 18.6%) as white solid.

Synthesis of Compound 4

Compound 3 (1 eq) was added to amine (20 mL). The reaction mixture wasstirred at 120° C. for 48 h. LC-MS showed that the starting material wasalmost consumed completely. The solvent was removed under vacuum. Theresidue was washed with DCM and concentrated under vacuum, affordedcompound 4.

Synthesis of Compound 5

A mixture of compound 4 (1.0 eq) and HMTA (4.0 eq) in TFA (100 mL) washeated to 90° C. under nitrogen for 2 h. LC-MS indicated that thereaction was completed. After cooled to RT, the solvent was removedunder vacuum. The residue was purified by Prep-HPLC, afforded compound5.

7-Hydroxy-5-methoxy-4-methyl-3-(3-morpholino-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 15% yield.

¹HNMR (CDCl₃, 400 MHz): δ 10.38 (s, 1H, CHO), 6.27 (s, 1H, ArH), 3.93(s, 3H, ArOCH₃), 3.70-3.56 (m, 8H, CH₂), 2.94-2.90 (m, 2H, CH₂), 2.58(s, 3H, CH₃), 2.58-2.53 (m, 2H, CH₂); MS [ESI, MH⁺]: 376.2.

7-Hydroxy-5-methoxy-4-methyl-3-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3. 9.2% yield. ¹HNMR(MeOD, 400 MHz): δ 10.30 (s, 1H, CHO), 6.44 (s, 1H, ArH), 3.97 (s, 3H,ArOCH₃), 3.29-3.27 (m, 5H, CH₂), 2.93 (s, 3H, CH₃), 2.92-2.87 (m, 4H,CH₂), 2.596-2.593 (m, 6H, CH₂); MS [ESI, MH⁺]: 389.2.

3-(8-Formyl-7-hydroxy-5-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 13% yield. ¹HNMR(CDCl3, 400 MHz): δ10.36 (s, 1H, CHO), 6.30 (s, 1H, —NH), 6.26 (s, 1H,ArH), 3.93 (s, 3H, ArOCH₃), 3.44-3.43 (m, 4H, 2CH₂), 3.31 (s, 3H, OCH₃),2.95 (t, 2H, J=8 Hz, CH₂), 2.56 (s, 3H, CH₃), 2.47 (t, 2H, J=8.0 Hz,CH₂). MS [ESI, MH⁺]: 364.1.

N-(2-(Dimethylamino)ethyl)-3-(8-formyl-7-hydroxy-5-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A1. 10% yield. ¹HNMR(D₂O, 400 MHz): δ9.72 (s, 1H, CHO), 6.10 (s, 1H, ArH), 6.26 (s, 1H,ArH), 3.81 (s, 3H, ArOCH₃), 3.59 (t, 2H, J=6.0 Hz CH₂), 3.32 (t, 2H,J=6.0 Hz CH₂), 2.95 (s, 6H, 2CH₃), 2.72 (t, 2H, J=7.6 Hz, CH₂). 2.39 (t,2H, J=7.6 Hz, CH₂), 2.37 (s, 3H, CH₃); MS [ESI, MH⁺]: 377.1.

3-(8-Formyl-7-hydroxy-5-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A5. 7.8% yield. ¹HNMR(MeOD, 400 MHz): δ 10.26 (s, 1H, CHO), 6.42 (s, 1H, —NH), 5.89 (s, 1H,ArH), 4.05 (s, 2H, CH₂), 3.96 (s, 3H, ArOCH₃), 3.87-3.51 (m, 8H, CH₂),3.14 (s, 2H, CH₂), 2.93 (t, 2H, J=7.6 Hz, CH₂), 2.56 (s, 3H, CH₃),2.43-2.36 (m, 2H, CH₂). MS [ESI, MH⁺]: 419.2.

Example 67

Synthesis of Compound 3

To a suspension of compound 1 (1 eq), compound 2 (1.2 eq), CH₃SO₃H wasadded in one portion. The mixture was stirred at RT 12 h. LC-MS showedthat starting material was consumed completely. The reaction mixture waspoured into ice-water (100 mL) and stirred for 30 min. The formedprecipitate was filtered and washed with water and EA, dried to affordthe crude compound 3 and use at the next step directly.

Synthesis of Compound 4

A mixture of compound 3 (1 eq) and HMTA (4 eq) in TFA was heated at 100°C. under nitrogen for 1.5h. The reaction mixture turned to dark-yellowin the period. LCMS indicated that the reaction was completed. Aftercooled to RT, the solvent was removed under reduced pressure, theproduct was purified by Prep-HPLC to give compound 4.

7-Hydroxy-6-methoxy-2-oxo-4-(trifluoromethyl)-2H-chromene-8-carbaldehydewas obtained by the above procedure from media A1. 39.6% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.69 (s, 1H, OH), 10.59 (s, 1H, CHO), 7.23 (s, 1H,ArH), 6.72 (s, 1H, CH), 3.96 (s, 3H, OCH₃); MS [ESI, MH⁺]: 289.0.

7-Hydroxy-8-methoxy-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromene-6-carbaldehydewas obtained by the above procedure from media A3. 8.9% yield. ¹H NMR(CDCl₃, 400 MHz): δ 12.47 (s, 1H, OH), 10.63 (s, 1H, CHO), 7.01 (s, 1H,ArH), 3.95 (s, 3H₂OCH₃), 3.08-3.04 (m, 2H, CH₂), 2.96-2.92 (m, 2H, CH₂),

2.25-2.22 (m, 2H, CH₂); MS [ESI, MH⁺]: 261.1.

7-Hydroxy-6-methoxy-3,4-dimethyl-2-oxo-2H-chromene-8-carbaldehyde wasobtained by the above procedure from media A3.1.2% yield. ¹H NMR (CDCl₃,400 MHz): δ 12.38 (s, 1H, OH), 10.61 (s, 1H, CHO), 7.18 (s, 1H, ArH),3.95 (s, 3H, OCH₃), 2.38 (d, 3H, J=8.0 HZ CH₃), 2.20 (d, 3H, J=8.0 HZCH₂); MS [ESI, MH⁺]: 249.1.

7-Hydroxy-3-isopropyl-6-methoxy-4-methyl-2-oxo-2H-chromene-8-carbaldehydewas obtained by the above procedure from media A4.5% yield. ¹H NMR(CDCl₃, 400 MHz): δ 12.38 (s, 1H, OH), 10.61 (s, 1H, CHO), 7.24 (d, 1H,J=14.8 HZ, ArH), 3.96 (s, 3H, OCH₃), 2.38 (m, 1H, CH), 2.41 (s, 3H,CH₃), 1.37-1.35 (m, 6H).

Example 68

Synthesis of Compound 1

To a solution of compound A (55 g, 179.74 mmol), 2-morpholinoethanol(23.5 g, 179.74 mmol) and triphenylphosphine (56.5 g, 215.69 mmol) inTHF, DIAD (43.5 g, 215.69 mmol) was added in portions. The solution wasstirred at ambient temperature over night. The reaction mixture wasconcentrated and purified by column chromatogram to give compound B(52.6 g, 69.8%). A slurry of compound B (52.6g, 125.54 mmol), CH₃COOH(100 mL) and Pd/C (14.0 g) in methanol (800 mL) was stirred at ambienttemperature for 4 hours under 2 atm H₂ (30 PSI). The mixture wasfiltered and filtrate was concentrated, the residue was purified bycolumn chromatogram y to give compound 1 (30 g, 98%).

Synthesis of Compound 3

A mixture of compound 1 (6.7 g, 28.0 mmol) and compound 2 (7.06 g, 28.0mmol) in methane sulfonic acid was stirred at ambient temperature overnight. The reaction mixture was poured into ice-water and stirred for 30minutes. The formed precipitate was filtered and washed with water andEA, dried to afford the compound 3 (5.0g, 44%).

Synthesis of Compound 4

Compound 3 (1.0 eq) was added to Amine (20 mL). The reaction mixture wasstirred at 120° C. for 48 h. LC-MS showed that the starting material wasalmost consumed completely. The solvent was removed under vacuum. Theresidue was washed with DCM (3×5 mL) and concentrated under vacuum,afforded compound 4.

Synthesis of Compound 5

A mixture of compound 4 (1.0 eq) and HMTA (4.0 eq) in TFA (100 mL) washeated to 90° C. under nitrogen for 2 h. LC-MS indicated that thereaction was completed. After cooled to RT, the solvent was removedunder vacuum. The residue was purified by Prep-HPLC, afforded Compound5.

3-(8-Formyl-7-hydroxy-4-methyl-6-(2-morpholinoethoxy)-2-oxo-2H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 10% yield. ¹HNMR(D₂O, 400 MHz): δ10.11 (s, 1H, CHO), 7.31 (s, 1H, ArH), 4.39 (t, J=4.4Hz, 2H, CH₂), 4.06 (d, J=12.4 Hz, 2H, CH₂), 3.79 (t, J=12.4 Hz, 2H,CH₂), 3.64-3.58 (m, 4H, CH₂), 3.32-3.25 (m, 4H, CH₂), 3.16 (t, J=5.6 Hz,2H, CH₂), 3.07 (s, 3H, OCH₃), 2.73 (t, J=7.6 Hz, 2H, CH₂), 2.32 (t,J=6.8 Hz, 2H, CH₂), 2.24 (s, 3H, CH₃); MS [ESI, MH⁺]: 462.23.

N-Ethyl-3-(8-formyl-7-hydroxy-4-methyl-6-(2-morpholinoethoxy)-2-oxo-2H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A4. 7.4% yield. ¹HNMR(D₂O, 400 MHz): δ9.97 (s, 1H, CHO), 7.25 (s, 1H, ArH), 4.35 (t, J=4.4Hz, 2H, CH₂), 4.03 (d, J=12.8 Hz, 2H, CH₂), 3.79 (t, J=12.8 Hz, 2H,CH₂), 3.61-3.55 (m, 4H, CH₂), 3.26-3.23 (m, 2H, CH₂), 2.95-2.64 (m, 4H),2.21-2.18 (m, 5H), 0.82 (t, J=7.2 Hz, CH₃; MS [ESI, MH⁺]: 433.2.

Example 69

Synthesis of 4-methoxybenzene-1,3-diol

To a solution of compound 1 (300 g, 1.98 mol) and SeO₂ (17.4 g, 0.15mol) in DCM (4 L) was added H₂O₂ (512 mL) dropwise at 0° C. The reactionmixture was stirred at RT for 16 h. The reaction was monitored by TLC.After the STM was consumed completely, the reaction mixture washed withaq. 10% NaHSO₃ (1 L), followed by Na₂CO₃ (1 L) and brine (1 L)successively, dried over Na₂SO₄, concentrated to get the crude compound2 without further purification. The crude compound 2 was dissolved in amixture of MeOH (3 L) and aq. 10% KOH (2 L) and stirred at RT overnight.After MeOH was removed, the mixture was acidified by 6M HCl to pH=3 andextracted with DCM (2 L×8). The combined DCM phase was washed with brineand dried over NaSO₄, concentrated. The residue was purified by silicagel column (EA:PE=6:1 to EA:PE=4:1) to give 4-methoxybenzene-1,3-diol(140 g, 50.5% yield) as light-yellow solid. ¹HNMR (MeOD, 400 MHz): δ6.70 (d, J=8.8 Hz, 1H, ArH), 6.29 (d, J=3.2 Hz, 1H, ArH), 6.18 (dd,J=8.8, 2.8 Hz, 1H, ArH), 3.73 (s, 3H, CH₃).

Synthesis of ethyl 4-(2,4-dihydroxy-5-methoxyphenyl)-4-oxobutanoate

To a suspension of compound 3 (15 g, 0.11 mol) and compound 4 (21 g,0.13 mol) in Dichloroethane (300 mL) was added BF₃C₂H₆O (15 g, 0.11 mol)in one portion. The mixture was stirred at RT for 4 h. After standingovernight, the reaction mixture was heated to reflux for 4 h, thencooled to RT. The formed precipitate was filtered and washed with waterand EA, dried to afford the crude ethyl4-(2,4-dihydroxy-5-methoxyphenyl)-4-oxobutanoate (20 g, 69% yield) asyellow oil. MS [ESI, MH⁺]: 268.1.

Synthesis of ethyl2-(7-acetoxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)acetate

The mixture of compound 5 (20 g, 0.07 mol), Ac₂O (31 g, 0.29 mol) andDBU (9 g, 0.55 mol) was heated to reflux for 6 h. After cooling to RT,the reaction mixture was dissolved in DCM (400 mL), then the solutionwas washed with water, dried over Na₂SO₄ and concentrated to give theethyl 2-(7-acetoxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)acetate (12g, 48% yield). MS [ESI, MNa⁺]: 356.9.

Synthesis of 2-(7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)acetic acid

The suspension of compound 6 (12.0 g, 0.036 mol) in 20% H₂SO₄ (80 mL)was heated to reflux for 4 h. After cooling to RT, the formedprecipitate was filtered, washed with water and EA, dried to give2-(7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)acetic acid (8 g,85%). MS [ESI, MNa⁺]: 286.8.

Synthesis of Compound 8

To the suspension of compound 7 (1 eq) and HATU (1 eq) in DMF was addedEt₃N (2 eq) dropwise at RT. The mixture was stirred at RT for 1 h. Thenamine (1.5 eq) was added. The reaction mixture was stirred at RT foranother 10 h. DMF was removed under vacuum, the residue was diluted withMeOH, the formed precipitate was filtered and washed with EA, dried togive compound 8.

Synthesis of Compound 9

A mixture of compound 8 (1 eq) and HMTA (4 eq) in HOAc was heated to 90°C. under N₂ for 1.5 h. The reaction was monitored by LCMS. After cooledto RT, the solvent was removed under vacuum; the residue was purified byprep-HPLC to give compound 9.

7-Hydroxy-6-methoxy-2-methyl-3-(2-morpholino-2-oxoethyl)-4-oxo-4H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 12% yield.

¹HNMR (CDCl₃, 400 MHz): δ 12.80 (s, 1H, OH), 10.53 (d, 1H, J=1.2 Hz,CHO), 7.68 (s, 1H, ArH), 3.97 (s, 3H, ArOCH₃), 3.77-3.61 (m, 10H), 2.53(s, 3H, CH₃). MS [ESI, MH⁺]: 362.0.

7-Hydroxy-6-methoxy-2-methyl-3-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-oxo-4H-chromene-8-carbaldehydehydrochloride was obtained by the above procedure from amine A3. 8%yield. ¹HNMR (MeOD, 400 MHz): δ 7.47 (s, 1H, ArH), 6.02 (s, 1H, CHO),3.93 (s, 3H, CH₃), 3.58-3.54 (m, 10H), 2.95 (s, 3H, CH₃), 2.45 (s, 3H,CH₃). MS [ESI, MH⁺]: 375.1.

N-Ethyl-2-(8-formyl-7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A4. 9% yield. ¹HNMR(CDCl₃, 400 MHz): δ 10.53 (d, 1H, J=0.8 Hz, CHO), 7.69 (s, 1H, ArH),6.50 (br, 1H, NH), 3.99 (s, 3H, ArOCH₃), 3.42 (s, 2H, CH₂), 3.22-3.18(m, 2H, CH₂), 2.62 (s, 3H, CH₃), 1.09 (t, 3H, J=0.8 Hz, CH₃). MS [ESI,MH⁺]: 320.1.

2-(8-Formyl-7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-morpholinoethyl)acetamidewas obtained by the above procedure from amine A5. 9% yield. ¹HNMR (D₂O,400 MHz): δ 10.21 (s, 1H, CHO), 7.26 (s, 1H, ArH), 4.14 (d, 2H, J=12.4Hz, CH₂), 3.88-3.82 (m, 6H, 3CH₂), 3.67 (t, 4H, J=6.0 Hz, 2CH₂), 3.53(s, 2H, CH₂), 3.40 (d, 2H, J=6.0 Hz, CH₂), 3.29-3.22 (m, 1H), 2.47 (s,3H, CH₃). MS [ESI, MH⁺]: 405.1.

N-(2-(dimethylamino)ethyl)-2-(8-formyl-7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A6. 8% yield. ¹HNMR (D₂O,400 MHz): δ 10.26 (s, 1H, CHO), 7.32 (s, 1H, ArH), 3.88 (s, 3H, CH₃),3.66 (t, 2H, J=5.6 Hz, CH₂), 3.56 (s, 2H, CH₂), 3.37 (t, 2H, J=5.6 Hz,CH₂), 2.97 (s, 6H, 2CH₃), 2.50 (s, 3H, CH₃). MS [ESI, MH⁺]: 363.1.

Example 70

Synthesis of Compound 3

To a suspension of compound 1 (15 g, 0.11 mol) and compound 2 (21 g,0.13 mol) in Dichloroethane (300 ml), BF₃C₂H₆O (15 g, 0.11 mol) wasadded in one portion. The mixture was first stirred at RT for 4 h, thenheated to reflux for 4 h. After cooling to RT, the formed precipitatewas filtered and washed with water and EA, dried to afford the crudecompound 3 (20 g, 69% yield) as yellow oil.

Synthesis of Compound 4

To a suspension of compound 3 (38 g, 0.15 mol) in EtOH (300 mL) wasadded H₂SO₄ (1 mL). The mixture was heated to reflux for 4 h. Aftercooling to RT, the reaction mixture was concentrated and purified bysilica gel column to give compound 4 (30 g, 75% yield) as yellow oil.

Synthesis of Compound 5

The mixture of compound 4 (30 g, 0.11 mol, Ac₂O (43.4 g, 0.42 mol) andDBU (15 g, 0.10 mol) was heated to reflux for 6 h. After cooled to RT,the reaction mixture was dissolved in DCM (400 mL), then the solutionwas washed with water, dried over Na₂SO₄ and concentrated to give thecompound 5 (19 g, 50% yield). ¹HNMR (CDCl₃, 400 MHz): δ 7.62 (s, 1H,ArH), 7.14 (s, 1H, ArH), 4.10 (q, 2H, J=7.2 Hz, CH₂), 3.91 (s, 3H, CH₃),2.84 (t, 2H, J=7.6 Hz, CH₂), 2.60 (t, 2H, J=7.6 Hz, CH₂), 2.46 (s, 3H,CH₃), 1.57 (s, 3H, CH₃), 1.22 (t, 3H, J=7.2 Hz, CH₃).

Synthesis of Compound 6

The suspension of compound 5 (19 g, 0.054 mol) in 20% H₂SO₄ (160 mL) washeated to reflux for 4 h, after cooling to RT, the formed precipitatewas filtered, washed water and EA, dried to give compound 6 (12 g, 80%).¹HNMR (MeOD, 400 MHz): δ 7.43 (s, 1H, ArH), 6.84 (s, 1H, ArH), 3.93 (s,3H, ArOCH₃), 2.81 (t, 2H, J=7.6 Hz, CH₂), 2.53 (q, 2H, J=7.6 Hz, CH₂),2.47 (s, 3H, CH₃).

Synthesis of Compound 7

To the suspension of compound 6 (1 eq) and HATU (1.05 eq) in DMF wasadded Et₃N (1.1 eq) dropwise at RT. Then the mixture was stirred at RTfor 1 h. Amine (1.1 eq) was added. The reaction mixture was stirred atRT for another 10 h. DMF was removed under vacuum. The residue wasdiluted with MeOH, the formed precipitate was filtered and washed withEA, dried to give compound 7.

Synthesis of Compound 8

A mixture of compound 7 (1 eq) and HMTA (4 eq) in HOAc was heated at120° C. under N₂ for 1.5 h. The reaction mixture was monitored by LCMS.After cooled to RT, the solvent was removed under vacuum; the residuewas purified by prep-HPLC to give compound 8.

3-(8-Formyl-7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 9% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.78 (s, 1H, OH), 10.54 (s, 1H, CHO), 7.72 (s, 1H,ArH), 6.03 (br, 1H, NH), 4.00 (s, 3H, ArOCH₃), 3.42 (s, 4H, 2CH₂), 3.31(s, 3H, OCH₃), 2.89 (t, J=6.8 Hz, 2H, CH₂), 2.55-2.51 (m, 5H). MS [ESI,MH⁺]: 364.0.

7-Hydroxy-6-methoxy-2-methyl-3-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-4-oxo-4H-chromene-8-carbaldehydehydrochloride was obtained by the above procedure from amine A3. 13%yield. ¹HNMR (D₂O, 400 MHz): δ 10.12 (s, 1H, CHO), 7.15 (s, 1H, ArH),4.62 (m, 1H), 4.28 (m, 1H), 3.82 (s, 3H, ArOCH₃), 3.63 (m, 3H), 3.24 (m,1H), 3.12 (m, 2H, CH₂), 2.98 (s, 3H, NCH₃), 2.66 (m, 4H), 2.43 (s, 3H,CH₃). MS [ESI, MH⁺]: 389.3

N-Ethyl-3-(8-formyl-7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A4. 9% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.78 (s, 1H, OH), 10.51 (s, 1H, CHO), 7.67 (s, 1H,ArH), 6.21 (br, 1H, NH), 3.97 (s, 3H, ArOCH₃), 3.25 (q, J=7.2 Hz, 2H,CH₂), 2.86 (t, 2H, J=7.2 Hz, CH₂), 2.53 (m, 5H), 1.08 (t, 3H, J=7.2 Hz,CH₃). MS [ESI, MH⁺]: 334.1.

3-(8-Formyl-7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-morpholinoethyl)propanamidehydrochloride was obtained by the above procedure from amine A5. 12%yield. ¹HNMR (D₂O, 400 MHz): δ 10.07 (s, 1H, CHO), 7.10 (s, 1H, ArH),4.13 (d, 2H, J=12.0 Hz, CH₂), 3.86 (d, 2H, J=12.0 Hz, CH₂), 3.78 (s, 3H,ArOCH₃), 3.62 (m, 4H, 2CH₂), 3.34 (t, 2H, J=6.0 Hz, CH₂), 3.23 (q, 2H,J=12.0 Hz, CH₂), 2.68 (t, 2H, J=8.0 Hz, CH₂), 2.43 (m, 5H). MS [ESI,MH⁺]: 419.2

N-(2-(Dimethylamino)ethyl)-3-(8-formyl-7-hydroxy-6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)propanamidehydrochloride was obtained by the above procedure from amine A6. 11%yield. ¹H NMR (D₂O, 400 MHz): δ 10.10 (s, 1H, CHO), 7.15 (s, 1H, ArH),3.80 (s, 3H, ArOCH₃), 3.58 (t, J=6.0 Hz, 2H, CH₂), 3.30 (t, 2H, J=6.0Hz, CH₂), 2.94 (s, 6H, 2CH₃), 2.70 (t, 2H, J=6.8 Hz, CH₂), 2.41 (m, 5H).MS [ESI, MH⁺]: 377.1.

Example 71

Synthesis of Compound 3

Glutaric anhydride dissolved in 3000 ml 1.2-DCE, the reaction mixturecooled to 0° C., AlCl₃ (138.3 g, 1.04 mol) added dropwise with stirringat 0° C., the above suspension added a solution of compound 1 (110.4 g,0.8 mol) in 600 ml of 1,2-DCE from the dropping funnel over a period of30 min. the mixture solution stirred at RT for 30 min, TLC (PE:EA=1:1)showed the starting material was consumed completely. The above solutionpoured into 1000 ml ice-water, the organic layers separated, the aqueouslayer was extracted with DCM (500*3), the combined organic layers werewashed with sat NaCl (500 ml*2), dried over Na₂SO₄, the solvent wasremoved to get the crude compound 2 and use at the next step directly.

The solution of the crude compound 2 in EtOH (1000 ml) and H₂SO₄ (10 ml)was heated to refluxed for 2 h, LC-MS showed the starting material wasconsumed completely. after cooled, the solvent was removed, the solidswas filtrated, washed with PE (300 ml) to give (160 g, 65%) compound 3as white solid.

MS [ESI, MH⁺]: 280.

Synthesis of Compound 4

To a solution of compound 3 (160 g, 0.57 mol) in dry DCM (1900 ml) wasadded BBr₃ (1142 g, 3.42 mol) in portions with stirring at −70° C., thereaction solution stirred at RT for 3 h, The reaction was quenched byaddition of 1000 ml of ethanol at −70° C., the solvent was removed, theresidue was chromatographed on silica gel (PE:EA=5:1) to give compound 4(80 g, 56%) as white solid. MS [ESI, MH⁺]: 253.0.

Synthesis of Compound 5

To a suspension of compound 4 (42.8 g, 0.17 mol) in AC₂O (69 g, 0.68mol) was added DBU (20.7 g, 0.14 mol) in one portion. The solutionstirred at 120° C. for 16h, TLC (PE:EA=5:1) showed the starting materialwas consumed completely. After cooled, the residue poured into 500 mlice-water, the reaction mixture was extracted with DCM (150*3), Thecombined organic layers dried, concentrated and chromatographed onsilica gel (PE:EA=5:1) to give compound 5 (40 g, 76%) as white solid.

Synthesis of Compound 6

The compound 5 (33 g, 0.103 mol) in 20% H₂SO₄ (500 ml) were heated to100° C. overnight, after cooled, the solids was filtrated, washed withDCM three times to give (20 g, 78%) compound 6 as white solid

Synthesis of Compound 7

To the suspension of Compound 6 (1 eq) and HATU (1.05 eq) in DMF wasadded Et₃N (1.1 eq) dropwise at RT, after the mixture was stirred atthis temperature for 1 h, amine (1.1 eq) was added, the reaction mixturewas stirred at RT for another 10 h, after DMF was eliminated, dilutedwith MeOH, the formed solid was filtered and washed with EA, dried togive Compound 7.

Synthesis of Compound 8

A mixture of compound 7 (1 eq) and HMTA (4 eq) in HOAc was heated at120° C. under nitrogen for 1.5 h. The reaction mixture turned todark-yellow in the period. LCMS indicated that the reaction wascompleted. After cooled to RT, the solvent was removed under reducedpressure, the product was purified by Prep-HPLC to give compound 8.

3-(8-Formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 4.1% yield. ¹HNMR(CDCl₃, 400 MHz) δ 12.40 (s, 1H, OH), 10.51 (s, 1H, CHO), 8.26 (d, 1H,J=9.2 HZ, ArH), 6.93 (d, 1H, J=9.2 HZ, ArH), 5.95 (s, 1H, OH), 3.38.3.37(m, 4H), 3.26 (s, 3H, CH₃), 2.83 (t, 2H, J=7.2 HZ, CH₂), 2.51 (s, 3H,CH₃), 2.47 (t, 2H, J=7.2 HZ, CH₂) MS [ESI, MH⁺]: 334.0

7-Hydroxy-2-methyl-3-(3-morpholino-3-oxopropyl)-4-oxo-4H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 3.6% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.35 (s, 1H, OH), 10.46 (s, 1H, CHO), 8.20 (d, 1H,J=8.8 HZ, ArH), 6.89 (d, 1H, J=9.2 HZ, ArH), 3.60-3.47 (m, 8H), 2.76 (t,2H, J=7.2 HZ, CH₂), 2.58 (t, 2H, J=7.2 HZ, CH₂), 2.50 (s, 3H, CH₃). MS[ESI, MH⁺]: 346.0

7-Hydroxy-2-methyl-3-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-4-oxo-4H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3. 9.2% yield. ¹HNMR(MeOD, 400 MHz): δ 7.95 (d, 1H, J=8.8 HZ, ArH), 6.89 (d, 1H, J=8.8 HZ,ArH), 6.06 (s, 1H, CHO), 3.61 (br, 6H), 3.01 (s, 3H, CH₃), 2.81 (t, 2H,J=7.6 HZ, CH₂), 2.56 (t, 2H, J=3.2 HZ, CH₂), 2.51 (s, 3H, CH₃). MS [ESI,MH⁺]: 359.2

N-Ethyl-3-(8-formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A4. 4.5% yield. ¹HNMR(CDCl₃, 400 MHz) δ 12.36 (s, 1H, OH), 10.46 (s, 1H, CHO), 8.21 (d, 1H,J=9.2 HZ, ArH), 6.88 (d, 1H, J=9.2 HZ, ArH), 5.67 (d, 1H, J=10 HZ, OH),3.17 (t, 2H, J=5.6 HZ, CH₂), 2.78 (t, 2H, J=5.6 HZ, CH₂), 2.47-2.39 (m,5H), 1.03-0.99 (m, 3H, CH₃). MS [ESI, MH⁺]: 304.0

N-(2-(Dimethylamino)ethyl)-3-(8-formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)propanamidewas obtained by the above procedure from amine A5. 5.4% yield. ¹HNMR(D₂O, 400 MHz) δ 10.06 (s, 1H, CHO), 7.78 (d, 1H, J=8.8 HZ, ArH), 6.74(d, 1H, J=8.8 HZ, ArH), 3.56 (t, 2H, J=6.0 HZ, CH₂), 3.29 (t, 2H, J=6.0HZ, CH₂), 2.91 (s, 6H). 2.64 (t, 2H, J=7.2 HZ, CH₂), 2.40 (t, 2H, J=7.2HZ, CH₂), 2.37 (s, 3H, CH₃,). MS [ESI, MH⁺]: 347.0

3-(8-Formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A6. 9.2% yield. ¹H NMR(D₂O, 400 MHz) δ 9.78 (s, 1H, CHO), 7.50 (d, 2H, J=8.8 HZ, ArH), 6.78(d, 1H, J=9.2 HZ, ArH), 3.91 (d, 1H, J=13.2 HZ, CH₂), 3.62 (t, 2H,J=13.2 HZ, CH₂), 3.38 (t, 2H, J=14.4 HZ, CH₂), 3.12 (t, 4H, J=6.0 HZ,CH₂), 3.04-2.97 (m, 4H), 2.41-2.13 (m, 7H) MS [ESI, MH⁺]: 389.1.

Example 72

Synthesis of Compound 2

Ethyl succinyl chloride (18 g, 0.11 mol) dissolved in 1.2-DCE (1000 ml),the reaction mixture cooled to 0° C., AlCl₃ (17.3 g, 0.13 mol) addeddropwise with stirring at 0° C., the above suspension added a solutionof compound 1 (13.8 g, 0.1 mol) in 200 ml of 1,2-DCE from the droppingfunnel over a period of 30 min, the mixture solution stirred at RT for30 min, TLC (PE:EA=1:1) showed the starting material was consumedcompletely. The above solution poured into 1000 ml ice-water, theorganic layers separated, the aqueous layer was extracted with DCM(500*3), the combined organic layers were washed with sat NaCl (500ml*2), dried over Na₂SO₄, the solvent was removed to get the crudecompound 2 (16 g, 60%) and use at the next step directly. MS [ESI, MH⁺]:267.

Synthesis of Compound 3

To a solution of compound 3 (23 g, 0.086 mol) in dry DCM (1345 ml) wasadded BBr₃ (173 g, 0.692 mol) in portions with stirring at −70° C., thereaction solution stirred at RT for 3h, The reaction was quenched byaddition of 1000 ml of ethanol, the solvent was removed, the residue waschromatographed on silica gel (PE:EA=5:1) to give compound 4 (12.2 g,60%)) as white solid.

Synthesis of Compound 4

To a suspension of compound 3 (7.5 g, 0.032 mol) in Ac₂O (13 g, 0.13mol) was added DBU (3.8 g, 0.025 mol) in one portion. The solutionstirred at 120° C. for 16h, TLC (PE:EA=1:1) showed the starting materialwas consumed completely. After cooled, the residue poured into 300 mlice-water, the reaction mixture was extracted with DCM (150*3), Thecombined organic layers dried, concentrated and chromatographed onsilica gel (PE:EA=5:1) to give compound 4 (9 g, 92%) as white solid. MS[ESI, MH⁺]: 305.2

Synthesis of Compound 5

The compound 4 (9 g, 0.030 mol) in 20% H₂SO₄ (200 ml) were heated to100° C. overnight, after cooled, the solids was filtrated, washed withDCM three times to give (5 g, 70%) compound 5 and use at the next stepdirectly. MS [ESI, MH⁺]: 234.8

Synthesis of Compound 6

To the suspension of Compound 5 (1 eq) and HATU (1.05 eq) in DMF wasadded Et₃N (1.1 eq) dropwise at RT, after the mixture was stirred atthis temperature for 1 h, amine (1.1 eq) was added, the reaction mixturewas stirred at RT for another 10 h, after DMF was eliminated, dilutedwith MeOH, the formed solid was filtered and washed with EA, dried togive Compound 6.

Synthesis of Compound 7

A mixture of compound 6 (1 eq) and HMTA (4 eq) in HOAc was heated at120° C. under nitrogen for 1.5h. The reaction mixture turned todark-yellow in the period. LCMS indicated that the reaction wascompleted. After cooled to RT, the solvent was removed under reducedpressure; the product was purified by Prep-HPLC to give compound 7.

2-(8-Formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-methoxyethyl)acetamidewas obtained by the above procedure from amine A1. 9.12% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.38 (s, 1H, OH), 10.47 (s, 1H, CHO), 8.23 (d, 1H,J=9.2 Hz, ArH), 6.91 (d, 1H, J=9.2 Hz ArH), 3.38-3.29 (m, 6H), 3.26 (s,3H, CH₃), 2.54 (s, 3H, CH₃) MS [ESI, MH⁺]: 320.0

7-Hydroxy-2-methyl-3-(2-morpholino-2-oxoethyl)-4-oxo-4H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 10% yield. ¹H NMR(CDCl₃, 400 MHz): δ 12.42 (br, 1H, OH), 10.54 (s, 1H, CHO), 8.28-8.25(m, 1H, ArH), 6.97-6.94 (m, 1H, ArH), 3.74-3.58 (m, 10H), 2.54 (s, 3H,CH₃). MS [ESI, MH⁺]: 332.1

7-Hydroxy-2-methyl-3-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-oxo-4H-chromene-8-carbaldehydewas obtained by the above procedure from amine A3. 7.3% yield. ¹HNMR(MeOD, 400 MHz): δ 7.96 (d, 1H, J=8.8 Hz, ArH), 6.92 (d, 1H, J=8.8 Hz,ArH), 6.08 (s, 1H, CHO), 4.70-4.40 (m, 2H, CH₂), 3.79-3.30 (m, 8H), 2.96(s, 3H, CH₃), 2.47 (s, 3H, CH₃). MS [ESI, MH⁺]: 345.1

N-Ethyl-2-(8-formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A4. 9.05% yield. ¹H NMR(CDCl₃, 400 MHz): δ 12.40 (br, 1H, OH), 10.48 (s, 1H, CHO), 8.22 (d, 1H,J=9.2 Hz, ArH), 6.92 (d, 1H, J=9.2 HZ, ArH), 6.43-6.36 (br, 1H, NH),3.35 (s, 2H, CH₃), 3.16-313 (q, 2H, J=7.2 HZ, CH₂), 2.56 (s, 3H, CH₃),1.03 (t, 3H, J=7.2 HZ CH₃), MS [ESI, MH⁺]: 290.0.

N-(2-(Dimethylamino)ethyl)-2-(8-formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)acetamidehydrochloride was obtained by the above procedure from amine A5. 9.2%yield. ¹H NMR (D₂O, 400 MHz): δ 10.02 (s, 1H, CHO), 7.72 (d, 1H, J=8.8Hz ArH), 6.66 (d, 1H, J=8.8 Hz, ArH), 3.47 (m, 2H, CH₂), 3.26 (m, 2H,CH₂), 3.18 (m, 2H, CH₂), 2.79 (s, 6H), 2.28 (s, 3H, CH₃) MS [ESI, MH⁺]:333.1

2-(8-Formyl-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-morpholinoethyl)acetamidewas obtained by the above procedure from amine A6. 18.6% yield ¹H NMR(D₂O, 400 MHz): δ 10.32 (s, 1H, CHO), 8.00 (d, 1H, J=9.2 HZ, ArH), 6.90(d, 1H, J=9.2 HZ, ArH), 4.10 (m, 2H, CH₂), 3.72 (m, 2H, CH₂) 3.55-3.09(m, 8H), 2.40 (s, 3H, CH₃), MS [ESI, MH⁺]: 375.

Example 73

Synthesis of Compound 2

Ethyl succinyl chloride (13.2 g, 0.08 mol) dissolved in 1.2-DCE (270ml), the reaction mixture cooled to 0° C., AlCl₃ (10.7 g, 0.08 mol) wasadded dropwise with stirring at 0° C., the above suspension added to asolution of compound 1 (9 g, 0.054 mol) in 1,2-DCE (30 ml) from thedropping funnel over a period of 30 min, the mixture solution stirred atRT for 30 min, TLC (PE:EA=1:1) showed the starting material was consumedcompletely. The above solution poured into ice-water (200 ml), theorganic layers separated, the aqueous layer was extracted with DCM(500*3), the combined organic layers were washed with sat NaCl (500ml*2), dried over Na₂SO₄ the solvent was removed to get the crudecompound 2 and use at the next step directly. MS [ESI, MH⁺]: 297.2.

Synthesis of Compound 3

The compound 2 (46 g, 0.145 mol), AlCl₃ (43 g, 0.324 mol) in dry DCM(240 ml) was was heated to 60° C. for 15 min and additional AlCl₃ (43 g,0.324 mol) was added followed by an additional 15 min. The reactionmixture heating at 60° C. for 2 h, LC-MS detected the starting materialwas consumed completely. The above suspension poured into ice-water(1000 ml), the organic layers separated, the aqueous layer was extractedwith DCM (500 mL×3), The combined organic layers dried, concentrated andchromatographed on silica gel (PE:EA=5:1) to give compound 3 (8 g, 21%)as white solid. MS [ESI, MH⁺]: 269.2

Synthesis of Compound 4

To a suspension of compound 3 (17 g, 0.063 mol) in Ac₂O (25.5 g, 0.25mol) was added DBU (8.5 g, 0.056 mol) in one portion. The solutionstirred at 120° C. for 16h, TLC (PE:EA=1:1) showed the starting materialwas consumed completely. After cooled to RT, the residue poured into 300ml ice-water, the reaction mixture was extracted with DCM (150*3), Thecombined organic layers dried, concentrated and chromatographed onsilica gel (PE:EA=5:1) to give compound 4 (10 g, 47.5%) as white solid.MS [ESI, MH⁺]: 334.8.

Synthesis of Compound 5

The compound 4 (10 g, 0.030 mol) in 20% H₂SO₄ (200 ml) were heated to100° C. overnight, after cooled, the solid was filtered, washed with DCMthree times to give (5 g, 63%) compound 5 and use at the next stepdirectly. MS [ESI, MH⁺]: 265.2.

Synthesis of Compound 6

To the suspension of Compound 5 (1 eq) and HATU (1.05 eq) in DMF wasadded Et₃N (1.1 eq) dropwise at RT, after the mixture was stirred atthis temperature for 1 h, amine (1.1 eq) was added, the reaction mixturewas stirred at RT for another 10 h, after DMF was eliminated, dilutedwith MeOH, the formed solid was filtered and washed with EA, dried togive Compound 6.

Synthesis of Compound 7

A mixture of compound 5 (1 eq) and HMTA (4 eq) in HOAc was heated at120° C. under nitrogen for 1.5 h. The reaction mixture turned todark-yellow in the period. LCMS indicated that the reaction wascompleted. After cooled to RT, the solvent was removed under reducedpressure; the product was purified by Prep-HPLC to give compound 6.

2-(8-Formyl-7-hydroxy-5-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)-N-(2-methoxyethyl)acetamidewas obtained by the above procedure from amine A1. 1.55% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.80 (s, 1H, OH), 10.29 (s, 1H, CHO), 6.68 (br, 1H,NH), 6.29 (s, 1H, ArH), 4.00 (s, 3H, OCH₃), 3.40-3.30 (m, 9H), 2.53 (s,3H, CH₃), MS [ESI, MH⁺]: 350.2.

7-Hydroxy-5-methoxy-2-methyl-3-(2-morpholino-2-oxoethyl)-4-oxo-4H-chromene-8-carbaldehydewas obtained by the above procedure from amine A2. 3.95% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.85 (br, 1H, OH), 10.29 (s, 1H, CHO), 6.29 (s, 1H,ArH), 3.94 (s, 3H, OCH₃), 3.75-3.63 (m, 8H), 3.53 (s, 2H, CH₂), 2.47 (s,3H, CH₃). MS [ESI, MH⁺]: 362.2.

N-Ethyl-2-(8-formyl-7-hydroxy-5-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)acetamidewas obtained by the above procedure from amine A4. 9.2% yield. ¹HNMR(CDCl₃, 400 MHz): δ 12.83 (br, 1H, OH), 10.29 (s, 1H, CHO), 6.88 (br,1H, NH), 6.31 (s, 1H, ArH), 4.00 (s, 3H, OCH₃), 3.37 (s, 2H, CH₂), 3.18(q, 2H, J=7.2 Hz, CH₂), 2.55 (s, 3H, CH₃), 1.07 (t, 3H, J=7.2 Hz, CH₃),MS [ESI, MH⁺]: 320.2.

Example 74

Synthesis of Compound 2

A mixture of compound 1 (1 eq) and amine was heated to 90° C. for 16 h.After cooling to room temperature, the reaction mixture was concentratedto give compound 2

Synthesis of Compound 3

To a solution of compound 1 (1.0 eq) in DMF/water (4:1) was added NaOH(2.0 eq) and MeI (1.2 eq) in turn. The reaction mixture was stirred atRT for 3 h, and then diluted with EtOAc (200 mL) and water (500 mL),extracted with EtOAc (200 mL×2), washed with brine (200 mL), dried overNa₂SO₄, concentrated to give the residue, and then purified bychromatography on silica gel to give compound 3

Synthesis of Compound 4

To a solution of compound 3 (1.0 eq) in DCM was added BBr₃ (2.0 eq) inDCM dropwise at −78° C. in 10 min and then warmed to RT and stirred for1 h. The reaction mixture was quenched with MeOH at −78° C.,concentrated to give the residue, and diluted with water (100 mL),washed with DCM. The aqueous layer was neutralized by 10% NaOH solutionto pH=8-9, then extracted with EtOAc (200 mL×3), dried over Na₂SO₄,concentrated to give compound 4.

Synthesis of Compound 5

A solution of Compound 4 (1.0 eq) and HMTA (4.0 eq) in AcOH was heatedto 90° C. for 16 h. After cooling to room temperature, the reactionmixture was concentrated to give the residue, and then purified byPrep-HPLC to give compound 5

6-Hydroxy-1-methyl-2-(3-morpholino-3-oxopropyl)-1H-benzo[d]imidazole-7-carbaldehydewas obtained by the above procedure from amine A2. 7.4% yield. ¹H NMR(D₂O, 400 MHz): δ 10.70 (s, 1H, CHO), 7.94 (d, J=9.2 Hz, 1H, ArH), 7.22(d, J=8.8 Hz, 1H, ArH), 4.24 (s, 3H, NCH₃), 3.78 (t, J=4.8 Hz, 2H, CH₂),3.73 (t, J=5.0 Hz, 2H, CH₂), 3.63 (t, J=4.8 Hz, 2H, CH₂), 3.57 (t, J=4.8Hz, 2H, CH₂), 3.50 (t, J=6.8 Hz, 2H, CH₂), 3.18 (t, J=6.8 Hz, 2H, CH₂).MS [ESI, MH⁺]: 318.2

N-Ethyl-3-(4-formyl-5-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)propanamidewas obtained by the above procedure from amine A4. 2.0% yield. ¹H NMR(MeOD, 400 MHz): δ 10.63 (s, 1H, CHO), 7.75 (d, J=9.2 Hz, 1H, ArH), 6.91(d, J=9.2 Hz, 1H, ArH), 3.87 (s, 3H, NCH₃) 3.25 (t, J=7.2 Hz, 2H, CH₂),3.19-3.14 (m, 2H, CH₂), 2.76 (t, J=4.8 Hz, 2H, CH₂), 1.06 (t, J=6.8 Hz,3H, CH₃). MS [ESI, MH⁺]: 276.2.

Example 75

Synthesis of Compound 2

To a mixture of compound 1 (33.6 g, 0.020 mol) and Pd/C (6.72 g) in MeOH(400 mL) was hydrogenated under 50 psi of H₂ at 50° C. for 3 h. Thecatalyst was filtered off and the filtrate was concentrated to give theresidue then purified by column chromatography on silica gel to givecompound 2 (20 g, 72.5%) as reddish solid.

Synthesis of Compound 3

A mixture of compound 2 (11 g, 79.7 mmol) and succinic anhydride (9.57g, 95.7 mmol) in dioxane (250 mL) was heated to 80° C. for 16 h. Thereaction mixture was concentrated to give the residue, and then dilutedwith EtOH (300 mL) and added conc. H₂SO₄ (5 mL). The suspension washeated to 80° C. for 16 h. After cooling to RT, the reaction mixture wasconcentrated to give the residue, diluted with water (200 mL),neutralized by 1 M NaOH solution to pH=7-8, extracted with DCM (500×3),washed with water (100 mL), brine (100 mL), dried over Na₂SO₄concentrated to give the residue, and then purified by chromatography onsilica gel to give compound 3 as yellow solid (13 g, 65.7%). ¹H NMR(th02877-062-1D₂O, 400 MHz): δ 7.43 (d, J=8.4 Hz, 1H, ArH), 7.01 (d,J=2.4 Hz, 1H, ArH), 6.87-6.84 (m, 1H, ArH), 4.20-4.15 (m, 2H, CH₂), 3.83(s, 3H, ArOCH₃), 3.19-3.16 (m, 2H, CH₂) 2.86-2.83 (m, 2H, CH₂) 1.26 (t,J=7.2 Hz, 4H, CH₂).

Synthesis of Compound 4

A mixture of compound 3 (1 eq) and amine was heated to 90° C. for 16 h.After cooling to RT, the reaction mixture was concentrated to givecompound 4 (1.9 g, 95.4%).

Synthesis of Compound 5

To a solution of Compound 4 (1 eq) in DCM was added BBr₃ (2.0 eq)dropwise at −78° C. over 10 min and then warmed to RT and stirred for 1.The reaction mixture was quenched with MeOH at −78° C., concentrated togive the residue, and diluted with water (100 mL), washed with DCM (50mL×3). The aqueous layer was neutralized by 10% NaOH solution to pH=8-9,then extracted with EtOAc (200 mL×3), dried over Na₂SO₄, concentrated togive compound 5.

Synthesis of Compound 6

A solution of compound 5 (1 eq) and HMTA (4.0 eq) in TFA was heated to90° C. for 1 h. After cooling to RT, the reaction mixture wasconcentrated to give the residue, and then purified by prep-HPLC to givecompound 6.

3-(4-Formyl-5-hydroxy-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 15.4% yield. ¹H NMR(D₂O, 400 MHz): δ 10.33 (s, 1H, CHO), 7.82 (d, J=9.2 Hz, 1H, ArH), 7.11(d, J=8.8 Hz, 1H, ArH), 3.50-3.44 (m, 4H, 2CH₂), 3.38 (d, J=5.2, Hz,CH₂), 3.27 (s, 3H, OCH₃), 2.92 (t, J=7.0 Hz, 2H, CH₂) MS [ESI, MH⁺]:292.2

5-Hydroxy-2-(3-morpholino-3-oxopropyl)-1H-benzo[d]imidazole-4-carbaldehydewas obtained by the above procedure from amine A2. 10.1% yield. ¹H NMR(DMSO, 400 MHz): δ 10.47 (s, 1H, CHO), 7.77 (d, J=8.8 Hz, 1H, ArH), 7.05(d, J=8.8 Hz, 1H, ArH), 5.06 (br, 1H, NH), 3.54 (d, J=4.4, 4H, 2CH₂),3.44 (t, J=4.6 Hz, 4H, 2CH₂), 3.24 (t, J=7.2 Hz, 2H, CH₂), 2.96 (t,J=7.2 Hz, 4H, CH₂) MS [ESI, MH⁺]: 304.2.

5-Hydroxy-2-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1H-benzo[d]imidazole-4-carbaldehydewas obtained by the above procedure from amine A3.16% yield. ¹H NMR(D20, 400 MHz): δ 10.40 (s, 1H, CHO), 7.86 (d, J=8.8 Hz, 1H, ArH), 7.17(d, J=9.2 Hz, 1H, ArH), 4.57 (d, J=7.0 Hz, 1H), 4.21 (d, J=15.6 Hz, 1H),3.63-3.58 (m 3H, CH₂), 3.47 (t, J=6.6 Hz, 2H, CH₂), 3.21 (m, 3H, CH₂),3.11-3.09 (m, 2H, CH₂), 2.95 (s, 3H, NCH₃); MS [ESI, MH⁺]: 317.2.

N-Ethyl-3-(4-formyl-5-hydroxy-1H-benzo[d]imidazol-2-yl)propanamide wasobtained by the above procedure from amine A4. 7.2% yield. ¹HNMR (M D₂O,400 MHz): δ 10.38 (s, 1H, CHO), 7.85 (d, J=8.8 Hz, 1H, ArH), 7.16 (d,J=9.2 Hz, 1H, ArH), 3.45 (t, J=2.8 Hz, 2H, CH₂), 3.15 (t, J=7.2 Hz, 2H,CH₂), 2.86 (t, J=7.2 Hz, 2H, CH₂), 1.03-1.01 (t, J=7.2 Hz, 3H, CH₃); MS[ESI, MH⁺]: 262.0.

3-(7-Formyl-6-hydroxy-1H-benzo[d]imidazol-2-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A5. 14.0% yield. ¹HNMR(D₂O, 400 MHz): δ 10.36 (s, 1H, CHO), 7.84 (d, J=9.2 Hz, 1H, ArH), 7.15(d, J=9.2 Hz, 1H, ArH), 4.10 (d, J=13.6 Hz, 2H, CH₂), 3.81 (d, J=12.0Hz, 2H, CH₂), 3.64-3.57 (m, 4H, CH₂), 3.46 (t, J=7.2 Hz, 2H, CH₂), 3.33(t, J=6.2 Hz, 2H, CH₂), 3.22 (d, J=5.2 Hz, 2H, CH₂), 2.96 (t, J=7.0 Hz,2H, CH₂); MS [ESI, MH⁺]: 347.3.

N-(2-(Dimethylamino)ethyl)-3-(4-formyl-5-hydroxy-1H-benzo[d]imidazol-2-yl)propanamidewas obtained by the above procedure from amine A6. 5.5% yield. ¹H NMR(MeOD, 400 MHz): δ 7.54 (d, J=8.8 Hz, 1H, ArH), 7.07 (d, J=8.8 Hz, 1H,ArH), 5.89 (s, 1H, CONH), 3.58 (t, J=5.8 Hz, 2H, CH₂), 3.44 (t, J=7.0Hz, 2H, CH₂), 3.29-3.27 (m, 2H, CH₂), 2.94 (t, J=4.8 Hz, 2H, CH₂), 2.92(s, 6H, 2NCH₃); MS [ESI, MH⁺]: 305.2.

Example 76

Synthesis of Compound 2

To a suspension of NaH (1.93 g, 48 mmol) in THF (100 mL) was addedcompound 1 (10 g, 40 mmol) in THF (100 mL) dropwise at 0° C. over 30min. The reaction mixture was stirred at RT for 1 h, and MeI (6.81 g, 48mmol) was added dropwise at 0° C. over 10 min. The mixture was stirredat RT for 16 h, then poured into ice water and extracted with EtOAc (1L×3), washed with brine (100 mL×3), dried over Na₂SO₄, concentrated togive (9.8 g, 86%) compound 2 as yellow solid. MS [ESI, MH⁺]: 263.1

Synthesis of Compound 3

To a solution of compound 2 (10 g, 38 mmol) in DCM (150 mL) was addedBBr₃ (19 g, 76 mmol) in DCM (50 mL) dropwise at −78° C. over 20 min. Thereaction mixture was warmed to RT and stirred at RT for 2 h, thenquenched with EtOH at −78° C. The mixture was diluted with water (50mL), then neutralized by adding sat. NaHCO₃ to pH=7-8, extracted withDCM (300 mL×4), washed with brine (100 mL), dried over Na₂SO₄,concentrated to give the residue, and then purified by columnchromatography on silica gel to give compound 3 (4.8 g, 51%) as yellowsolid.

Synthesis of Compound 4

A mixture of compound 3 (2.47 g, 10 mmol) and HMTA (5.58 g, 40 mmol) inTFA (120 mL) was heated to 90° C. for 18 h. After cooling to RT, thereaction mixture was concentrated to give the residue, and then dilutedwith water (100 mL), extracted with EtOAc (500 mL×2), washed with brine(100 mL×2), dried over Na₂SO₄, concentrated to give the crude product,then purified by column chromatography on silica gel to give yellowsolid and further purified by SFC to give compound 4 (0.5 g, 18%) asyellow solid.

Synthesis of Compound 5

A mixture of compound 4 (0.9 g, 3.26 mmol) and 6 M HCl (30 mL) solutionwas heated to 100° C. for 2 h. The solvent was removed under vacuum togive compound 5 (0.8 g, 86.5%) as reddish solid.

Synthesis of Compound 6

To a suspension of compound 5 (1.0 eq) in DCM was added PyBop (1.2 eq)and DIEA (2.5 eq). The mixture was stirred at RT for 30 min, and thenadded amine (1.2 eq). The reaction mixture was stirred at RT for 1 h.The solvent was removed to give the residue, purified by Prep-HPLC togive compound 6

3-(7-Formyl-6-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1 25% yield. ¹HNMR(MeOD, 400 MHz): δ 10.68 (s, 1H, CHO), 7.73 (d, J=8.8 Hz, 1H, ArH), 6.81(d, J=8.4 Hz, 1H, ArH), 4.02 (s, 3H, NCH₃), 3.43-3.40 (m, 2H, CH₂),3.36-3.33 (m, 2H, CH₂), 3.31-3.29 (m, 3H, OCH₃), 3.19 (t, J=7.4 Hz, 2H,CH₂), 2.76 (t, J=7.6 Hz, 2H, CH₂) MS [ESI, MH⁺]: 306.2

3-(7-Formyl-6-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A3. 28.6% yield. ¹HNMR(D₂O, 400 MHz): δ 10.70 (s, 1H, CHO), 7.95 (d, J=9.2 Hz, 1H, ArH), 7.23(d, J=8.8 Hz, 1H, ArH), 4.23 (s, 3H, NCH₃), 4.12 (d, J=6.4 Hz, 2H, CH₂),3.81 (t, J=12.6 Hz, 2H, CH₂), 3.64 (m, 4H, 2CH₂), 3.58-3.51 (m, 2H,CH₂), 3.34 (t, J=6.2 Hz, 2H, CH₂), 3.26-3.20 (m, 2H, CH₂), 2.97 (t,J=7.4 Hz, 2H) MS [ESI, MH⁺]: 361.1.

6-Hydroxy-1-methyl-2-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1H-benzo[d]imidazole-7-carbaldehydewas obtained by the above procedure from amine A5. 14.1% yield. ¹HNMR (MD₂O, 400 MHz): δ 10.69 (s, 1H, CHO), 7.93 (d, J=9.2 Hz, 1H, ArH), 7.20(d, J=9.2 Hz, 1H, ArH), 4.53 (t, J=5.4 Hz, 1H), 4.22 (s, 4H), 3.69 (d,J=8.0 Hz, 3H, CH₂), 3.51 (t, J=6.2 Hz, 2H, CH₂), 3.21 (t, J=7.0 Hz, 3H,CH₂), 3.10 (t, J=5.2 Hz, 2H, CH₂), 2.95 (s, 3H, NCH₃); MS [ESI, MH⁺]:331.3.

3-(7-Formyl-6-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)propanoic acid

¹HNMR (D₂O, 400 MHz): δ 10.60 (s, 1H, CHO), 7.86 (d, J=9.2 Hz, 1H, ArH),7.11 (d, J=9.2 Hz, 1H, ArH), 4.17 (s, 3H, NCH₃), 3.48 (t, J=7.0 Hz, 2H,CH₂), 3.03 (t, J=7.0 Hz, 2H, CH₂); MS [ESI, MH⁺]: 249.1.

Example 77

Synthesis of Compound 2

To a suspension of NaH (14.9 g, 0.373 mol) in DMF (1 L) was addedcompound 1 (50 g, 0.298 mol) in DMF (200 mL) dropwise at ° C. over 1 h.The reaction mixture was stirred at RT for 1 h, and then MeI (46.5 g,0.328 mol) was added. The reaction mixture was stirred at RT for 16 h,and then poured into ice water. The mixture was concentrated to give theresidue, diluted with DCM (3 L), washed with water (200 mL×2), brine(200 mL×2), dried over Na₂SO₄, concentrated to give compound 2 (50 g,92.6%) as reddish solid.

Synthesis of Compound 3

To a mixture of compound 2 (40 g, 0.22 mol) and Pd/C (9.0 g) in MeOH(1.0 L) was hydrogenated under 40 psi H₂ at 30° C. for 16 h. Thecatalyst was filtered off and the filtrate was concentrated to give theresidue then purified by column chromatography on silica gel to givecompound 3 (30 g, 91%) as brown solid.

Synthesis of Compound 4

A mixture of compound 3 (30 g, 0.197 mol) and succinic anhydride (23.7g, 0.237 mol) in dioxane (500 mL) was heated to 80° C. for 16 h. Thereaction mixture was concentrated to give the residue. The residue wasdiluted with EtOH (500 mL) and added conc. H₂SO₄ (10 mL). The suspensionwas heated to 90° C. for 16 h. After cooling to RT, the reaction mixturewas concentrated to give the residue, diluted with water (400 mL),neutralized by adding 1 M NaOH solution to pH=7-8, extracted with DCM(500 mL×3), washed with water (100 mL), brine (100 mL), dried overNa₂SO₄ concentrated to give the residue, and then purified bychromatography on silica gel to give compound 4 as yellow solid (23 g,44%). MS [ESI, MH⁺]: 263.2.

Synthesis of Compound 5

To a solution of compound 4 (22 g, 0.084 mol) in DCM (250 mL) was addedBBr₃ (42 g, 0.168 mol) dropwise at −78° C. over 20 min and then warmedto RT and stirred for 1 h. The reaction mixture was quenched with MeOHat −78° C., concentrated to give the residue, neutralized by 10% NaOHsolution to pH=8-9, then extracted with EtOAc (200 mL×3), dried overNa₂SO₄, concentrated to give compound 5 (5.0 g, 24%) as yellow solid.¹HNMR (MeOD, 400 MHz): δ1 7.21 (d, J=8.4 Hz, 1H, ArH), 6.94 (d, J=2.0Hz, 1H, ArH), 6.78-6.75 (m, 1H, ArH), 3.72 (s, 3H, NCH₃), 3.09 (t, J=7.2Hz, 2H, CH₂), 2.88 (t, J=7.2 Hz, 2H, CH₂), 1.18 (t, J=7.0 Hz, 3H, CH₃).

Synthesis of Compound 6

A solution of compound 5 (5.0 g, 0.020 mol) and HMTA (11.3 g, 0.080 mol)in TFA (150 mL) was heated to 90° C. for 16 h. After cooling to RT thereaction mixture was concentrated to give the residue, diluted withwater (100 mL), and then extracted with EtOAc (500 mL), washed withwater (50 mL×3), brine (100 mL), dried over Na₂SO4 to give the crudeproduct and then purified by column chromatography on silica gel to givecompound 6 (1.3 g, 23.6%) as yellow solid.

Synthesis of Compound 7

A mixture of compound 6 (1.3 g, 4.71 mmol) in 6 M HCl solution (40 mL)was heated to 90° C. for 1 h. The reaction mixture was concentrated togive the product (1.05 g, 68%) as red solid.

Synthesis of Compound 8

A suspension of compound 7 (1.0 eq), PyBop (1.2 eq) and DIEA (2.5 eq) inDCM (3 mL) was stirred at RT for 30 min, then added amine (1.0 eq). Themixture was stirred at RT for 16 h, diluted with DCM (200 mL), washedwith water (20 mL×3), dried over Na₂SO₄, concentrated to give theresidue, then purified by prep. TLC to give compound 8

3-(4-Formyl-5-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 18.5% yield. ¹H NMR(CDCl₃, 400 MHz): δ 11.45 (s, 1H, OH), 10.74 (s, 1H, CHO), 7.43 (d,J=8.8 Hz, 1H, ArH), 6.84 (d, J=8.4 Hz, 1H, ArH), 6.65 (br, 1H, NH), 3.76(s, 3H, NCH₃), 3.41 (t, J=3.8 Hz, 2H, CH₂), 3.29 (s, 3H, OCH₃), 3.19 (t,J=6.8 Hz, 2H, CH₂), 2.88 (t, J=6.6 Hz, 2H, CH₂); MS [ESI, MH⁺]: 306.2.

5-Hydroxy-1-methyl-2-(3-morpholino-3-oxopropyl)-1H-benzo[d]imidazole-4-carbaldehydewas obtained by the above procedure from amine A2. 24.7% yield. ¹H NMR(DMSO, 400 MHz): δ 11.69 (s, 1H, OH), 10.46 (s, 1H, CHO), 8.09 (d, J=8.8Hz, 1H, ArH), 7.28 (d, J=8.8 Hz, 1H, ArH), 3.98 (s, 3H, NCH₃), 3.56 (t,J=4.6 Hz, 2H, CH₂), 3.51 (t, J=5.0 Hz, 2H, CH₂), 3.39 (s, 4H, 2CH₂),3.31 (t, 2H, J=5.2 Hz, CH₂), 2.98 (t, 2H, J=5.2 Hz, CH₂); MS [ESI, MH⁺]:318.2.

3-(4-Formyl-5-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A5. 12.6% yield. ¹H NMR(CDCl₃ 400 MHz): δ 11.42 (s, 1H, OH), 10.73 (s, 1H, CHO), 7.42 (d, J=8.8Hz, 1H, ArH), 6.84 (d, J=8.8 Hz, 1H, ArH), 6.54-6.51 (br, 1H, NH), 3.77(s, 3H, NCH₃), 3.68 (t, J=3.8 Hz, 4H, 2CH₂), 3.36 (d, J=5.6 Hz, 2H,CH₂), 3.20 (t, J=7.0 Hz, 2H, CH₂), 2.89 (d, J=7.2 Hz, 2H, CH₂), 2.45 (s,6H); MS [ESI, MH⁺]: 361.3

5-Hydroxy-1-methyl-2-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1H-benzo[d]imidazole-4-carbaldehydewas obtained by the above procedure from amine A3. 6.9% yield. ¹H NMR(CDCl₃, 400 MHz): δ 11.45 (s, 1H, OH), 10.73 (s, 1H, CHO), 7.43 (d,J=8.8 Hz, 1H, ArH), 6.83 (d, J=9.2 Hz, 1H, ArH), 3.80 (s, 3H, NCH₃),3.63-3.58 (m, 4H, 2CH₂), 3.21 (t, J=6.8 Hz, 2H, CH₂), 3.03 (d, J=7.0 Hz,2H, CH₂), 2.44-2.38 (m, 4H, 2CH₂), 2.31 (s, 3H, NCH₃); MS [ESI, MH⁺]:331.3.

Ethyl 3-(4-formyl-5-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)propanoate

¹H NMR (CDCl₃, 400 MHz): δ 11.45 (s, 1H, OH), 10.72 (d, J=0.4 Hz 1H,CHO), 7.43 (d, J=8.8 Hz, 1H, ArH), 6.83 (d, J=8.8 Hz, 1H, ArH),4.18-4.13 (m, 2H, CH₂), 3.77 (s, 3H, NCH₃), 3.16 (t, J=4.8 Hz, 2H, CH₂),2.99 (t, J=4.8 Hz, 2H, CH₂), 1.24 (t, J=7.2 Hz, 3H, CH₃); MS [ESI, MH⁺]:=277.2

3-(4-Formyl-5-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)propanoic acid

¹H NMR (D₂O, 400 MHz): δ 10.35 (s, 1H, CHO), 7.91 (d, J=8.8 Hz, 1H,ArH), 7.19 (d, J=9.2 Hz, 1H, ArH), 4.03 (s, 3H, NCH₃), 3.49 (t, J=7.2Hz, 2H, CH₂), 3.02 (t, J=7.0 Hz, 2H, CH₂); MS [ESI, MH⁺]: 249.2.

Example 78

Synthesis of Compound 2

Compound 1 (60.0 g, 355.0 mmol) and Pd/C (8 g) were added to EA/MeOH(320 mL/480 mL). The reaction mixture was stirred at RT under H₂ (30Psi) for 4 h and filtered through Celite pad. The filter wasconcentrated, afforded the crude product. The crude product was washedwith MTBE (100 mL), dried, afforded compound 2 (45.0 g, 91.1%) as brownsolid.

Synthesis of Compound 3

Compound 2 (32.5 g, 233.8 mmol) and Et₃N (23.6 g, 233.8 mmol) were addedto DCM (650 mL). The solution of acylchloride (38.5 g, 234.7 mmol) inDCM (200 mL) was added dropwise. Then the mixture was warmed slowly toRT and stirred for 3 h. The reaction mixture was diluted with DCM (500mL), washed with 1N HCl (100 mL) and brine ((200 mL×2). The DCM layerwas dried over Na₂SO₄, filtered, concentrated, afforded crude compound 3(52.0 g, ˜40% purity) as brown oil.

Synthesis of Compound 4

Compound 3 (40.0 g, 149.8 mmol) and PPTS (12.5 g, 49.8 mmol) were addedto xylene (600 mL). The mixture was heated to 140° C. for 16 h. Aftercooled to RT, the reaction mixture was concentrated, purified by silicagel column (PE:EA=5:1), afforded compound 4 (10.0 g, 66.9%) as light redsolid.

Synthesis of Compound 5

Compound 4 (12.6 g, 50.60 mmol) was dissolved in dry DCM (225 mL),cooled to −60° C. The solution of BBr₃ (75.6 g, 302.4 mmol) in DCM (225mL) was added dropwise. Then the reaction mixture was warmed slowly toRT and stirred for another 2 h. The reaction was quenched with EtOH (17mL) at −60° C. The reaction mixture was concentrated. The residue wasdiluted with H₂O (200 mL), extracted with EA (100 mL×3). The combined EAwas washed with sat. NaHCO₃ (100 mL×2), dried over Na₂SO₄, filtered,concentrated, purified by silica gel column (PE:EA=3:1), affordedcompound 5 (9.2 g, 77.3%) as light yellow solid.

Synthesis of Compound 6

Compound 5 (4.0 g, 17.02 mmol) and HMTA (9.53 g, 68.07 mmol) were addedto TFA (225 mL). The reaction mixture was heated to 90˜95° C. for 2 h.The reaction mixture was concentrated. The residue was diluted with H₂O(100 mL), extracted with EA (80 mL×2). The combined EA was washed withsat. NaHCO₃, dried over Na₂SO₄, filtered, concentrated, purified bysilica gel column (PE:EA=10:1), afforded compound 6 (2.0 g, 44.6%) aswhite solid. ¹HNMR (CDCl₃, 400 MHz): δ 11.26 (s, 1H, OH), 10.57 (s, 1H,CHO), 7.61 (d, J=9.2 Hz, 1H, ArH), 6.89 (d, J=9.2 Hz, 1H, ArH), 4.17 (q,J=7.2 Hz, 2H, CH₂), 3.27 (t, J=7.2 Hz, 2H, CH₂), 2.94 (t, J=7.2 Hz, 2H,CH₂), 1.26 (t, J=7.2 Hz, 3H, CH₃). MS [ESI, MH⁺]: 264.2

Synthesis of Compound 7

Compound 6 (2.0 g, 7.6 mmol) was added to THF/H₂O (25 mL/12 mL),LiOH.H₂O (1.16 g, 27.6 mmol) was added. The reaction mixture was stirredat RT for 30 min and quenched with 1N HCl (30 mL). Then the mixture wasextracted with EA (15 mL×2). The combined EA was washed with brine,dried over Na₂SO₄, filtered, concentrated, afforded compound 7 (1.6 g,89.4%) as white solid. ¹HNMR (DMSO, 400 MHz): δ 12.39 (br, 1H, COOH),10.92 (br, 1H, OH), 10.48 (s, 1H, —CHO), 7.90 (d, J=8.8 Hz, 1H, ArH),6.94 (d, J=8.8 Hz, 1H, ArH), 3.17 (t, J=7.2 Hz, 2H, CH₂), 2.83 (t, J=7.2Hz, 2H, CH₂). MS [ESI, MH⁺]: 236.1

Synthesis of Compound 8

Compound 7 (1 eq) and CDI (1.1 eq) were added to dry DCM. The reactionmixture was stirred at RT for 0.5 h. The solution of amine (1 eq) in DCMwas added dropwise at RT. Then the reaction mixture was stirred at RTfor 16 h. LC-MS indicated that the reaction was completed. The mixturewas diluted with DCM, washed with H₂O, dried over Na₂SO₄, concentrated.The crude product was purified by silica gel column, afforded compound8.

3-(4-Formyl-5-hydroxybenzo[d]oxazol-2-yl)-N-(2-methoxyethyl)propanamidewas obtained by the above procedure from amine A1. 26.8% yield. ¹HNMR(CDCl₃, 400 MHz): δ 11.25 (s, 1H, OH), 10.57 (s, 1H, CHO), 7.60 (d,J=9.2 Hz, 1H, ArH), 6.88 (d, J=9.2 Hz, 1H, ArH), 6.14 (br, 1H, NH),3.45-3.43 (m, 4H, 2CH₂), 3.33 (s, 3H, OCH₃), 3.30 (t, J=7.2 Hz, 2H,CH₂), 2.81 (t, J=7.2 Hz, 2H, CH₂). MS [ESI, MH⁺]: 293.2.

5-Hydroxy-2-(3-morpholino-3-oxopropyl)benzo[d]oxazole-4-carbaldehyde wasobtained by the above procedure from amine A2. 42.6% yield. ¹HNMR(CDCl₃, 400 MHz): δ 11.26 (s, 1H, OH), 10.57 (s, 1H, CHO), 7.61 (d,J=9.2 Hz, 1H, ArH), 3.73-3.63 (m, 4H, 2CH₂), 3.57-3.54 (m, 2H, CH₂),3.34-3.30 (m, 2H, CH₂), 3.32 (t, J=7.2 Hz, 2H, CH₂), 2.96 (t, J=7.2 Hz,2H, CH₂). MS [ESI, MH⁺]: 305.2.

5-Hydroxy-2-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)benzo[d]oxazole-4-carbaldehydewas obtained by the above procedure from amine A3. 20% yield. ¹HNMR(CDCl₃, 400 MHz): δ 10.56 (s, 1H, CHO), 7.59 (d, J=8.8 Hz, 1H, ArH),6.86 (d, J=8.8 Hz, 1H, ArH), 3.66-3.63 (m, 2H, CH₂), 3.57-3.55 (m, 2H,CH₂), 3.30 (t, J=7.2 Hz, 2H, CH₂), 2.95 (t, J=7.2 Hz, 2H, CH₂),2.45-2.44 (m, 2H, CH₂), 2.43-2.39 (m, 2H, CH₂), 2.31 (s, 3H, CH₃). MS[ESI, MH⁺]: 318.2.

N-Ethyl-3-(4-formyl-5-hydroxybenzo[d]oxazol-2-yl)propanamide wasobtained by the above procedure from amine A4. 38.9% yield. ¹HNMR(CDCl₃, 400 MHz): δ 10.56 (s, 1H, CHO), 7.77 (d, J=8.8 Hz, 1H, ArH),6.93 (d, J=8.8 Hz, 1H, ArH), 3.32 (t, J=7.2 Hz, 2H, CH₂), 3.21 (q, J=7.2Hz, 2H, CH₂), 2.81 (t, J=7.2 Hz, 2H, CH₂), 1.11 (t, J=7.2 Hz, 3H, CH₃).MS [ESI, MH⁺]: 263.2.

3-(4-Formyl-5-hydroxybenzo[d]oxazol-2-yl)-N-(2-morpholinoethyl)propanamidewas obtained by the above procedure from amine A5. 10.2% yield. ¹HNMR(CDCl₃, 400 MHz): δ 11.24 (s, 1H, OH), 10.57 (s, 1H, CHO), 7.61 (d,J=8.8 Hz, 1H, ArH), 6.89 (d, J=8.8 Hz, 1H, ArH), 6.15 (br, 1H, NH),3.70-3.67 (m, 4H, 2CH₂), 3.40-3.35 (m, 2H, CH₂), 3.31 (t, J=7.2 Hz, 2H,CH₂), 2.83 (t, J=7.2 Hz, 2H, CH₂), 2.48-2.43 (m, 6H, 3CH₂). MS [ESI,MH⁺]: 348.2.

Example 79

Synthesis of Compound 2

Compound 1 (25 g, 294.1 mmol) and DMF (0.5 mL) were suspended in DCM(250 mL). (COCl)₂ (41 g, 323.5 mmol) was added dropwise at 0° C. Afterthat the reaction mixture was stirred at RT for 4 h. The reactionmixture was concentrate. The residue was dissolved in dry DCM (250 mL).The solution of acyl chloride was added dropwise to the solutionmorpholine (28.1 g, 323.5 mmol) and Et₃N (32.7 g, 323.5 mmol) in DCM(100 mL) at 0° C. Then the mixture was stirred at RT for 16 h andconcentrated. The residue was purified by silica gel column (DCM:MeOH=20:1), afforded compound 2 (18.7 g, 41%) as white solid.

Synthesis of Compound 3

Compound 2 (18.5 g, 120.1 mmol) and EtOH (8.3 mmol) were added to CHCl₃(120 mL), cooled to −20° C. HCl (gas) was bubble into the mixture for 1h. Then the reaction mixture was stirred at RT for another 1.5 h. Thesolvent was removed under vacuum. The residue was washed with MTBE,afforded compound 3 (14.5 g, 51%) as white solid.

Synthesis of Compound 5

Compound 3 (12.2 g, 51.5 mmol) was dissolved in MeOH (105 mL), cooled to0° C. The solution of compound 4 (6 g, 43.1 mmol) in MeOH (60 mL) wasadded dropwise. The reaction mixture was stirred at RT for 16 h. Thereaction mixture was concentrated, purified by silica gel column(PE:EA=2:1), afforded compound 5 (8.7 g, 73.1%) as white solid.

Synthesis of Compound 6

t-BuOK (4.2 g, 38.7 mmol) was suspended in THF (100 mL), cooled to 0° C.The solution of compound 5 (8.7 g, 32.2 mmol) in THF (75 mL) was addeddropwise and stirred for 1 h. The solution of MeI (4.7 g, 33.8 mmol) inTHF (25 mL) was added dropwise at 0° C., then stirred at RT for another4 h. The reaction mixture was quenched with H2O, acidified by 2 N HCl top H=4, extracted with EA, concentrated. The residue was purified bysilica gel column (PE:EA=2:1), afforded compound 6 (7.3 g, 80.2%) aswhite solid.

Synthesis of Compound 7

Compound 6 (5.8 g, 20 mmol) was dissolved in DCM (120 mL), cooled to−60° C. The solution of BBr₃ (30 g, 120 mmol) in DCM (40 mL) was addedat −60° C. After that, the reaction mixture was stirred at RT for 1 h.Then the reaction was quenched with H2O, extracted with EA. The combinedEA was dried over Na₂SO₄, filtered, concentrated. The residue waspurified by silica gel column (PE:EA=1:2), afforded compound 7 (3.3 g,47.8%) as white solid. ¹HNMR (CDCl₃, 400 MHz): δ 7.28 (dd, J=8.8 Hz, 2.4Hz, 1H, ArH), 7.16 (d, J=2.4 Hz, 1H, ArH), 6.82 (dd, J=8.8 Hz, 2.4 Hz,1H, ArH), 4.30 (q, J=6.8 Hz, 1H, CH), 3.75-3.55 (m, 8H, 4CH₂), 1.70 (d,J=6.8 Hz, 3H, CH₃).

Synthesis of5-hydroxy-2-(1-morpholino-1-oxopropan-2-yl)benzo[d]oxazole-4-carbaldehyde

Compound 7 (1 g, 3.62 mmol) and HMTA (2.1 g, 14.5 mmol) were added toTFA (45 mL). The reaction mixture was heated to 95° C. for 1 h. Thereaction mixture was concentrated. The residue was purified by prep-HPLCand prep-TLC successively, afforded5-hydroxy-2-(1-morpholino-1-oxopropan-2-yl)benzo[d]oxazole-4-carbaldehyde(200 mg, 12.1%) as yellow solid. MS [ESI, MH⁺]: 305.2.

Example 80

Synthesis of Compound 2

Compound 1 (100 g, 657 mmol) and NH₂OH.HCl (137 g, 1973 mmol) were addedto EtOH (1.5 L). The reaction mixture was refluxed for 16 h. Thereaction mixture was concentrated. The residue was recrystallized fromDCM/PE (4:1), afforded compound 2 (95 g, 86.4% yield). ¹HNMR (MeOD, 400MHz): δ 6.88 (q, J=1.2 Hz, 1H, ArH), 6.688-6.682 (m, 2H), 2.25 (s, 3H).

Synthesis of Compound 3

Compound 2 (20.0 g, 119.7 mmol) was dissolved in DMF (300 mL), cooled to0° C. POCl₃ (20 g, 131.6 mmol) was added dropwise keeping the innertemperature below 10° C. Then the reaction mixture was stirred foranother 1 h. H₂O (1 L) was added to the reaction mixture, extracted withEA (300 mL×3). The combined EA was concentrated. The residue wasdissolved in MTBE (800 mL), washed with H₂O (200 mL×3). The organiclayer was dried over Na₂SO₄, concentrated. The residue was washed withDCM/PE (4:1) (250 mL), afforded compound 3 (13.5 g, 75.6%). ¹HNMR (MeOD,400 MHz): δ 7.32 (d, J=8.8 Hz, 1H, ArH), 6.95 (s, 1H, ArH), 6.79 (d,J=8.8 Hz, 1H, ArH), 2.56 (s, 3H).

5-hydroxy-2-methylbenzo[d]oxazole-4-carbaldehyde2

Compound 3 (1.5 g, 10.06 mmol) and HMTA (5.6 g, 40.0 mmol) were added toTFA (100 mL). The mixture was heated to 90° C. for 1 h. After cooled toRT, the reaction mixture was concentrated, purified by prep-HPLC andprep-TLC successively, afforded5-hydroxy-2-methylbenzo[d]oxazole-4-carbaldehyde (20.0 mg, 1.1%) asyellow solid. ¹HNMR (CDCl₃, 400 MHz): δ 11.27 (s, 1H, OH), 10.58 (s, 1H,CHO), 7.60 (d, J=8.8 Hz, 1H, ArH), 6.88 (d, J=8.8 Hz, 1H, ArH), 2.67 (s,3H, CH₃). MS [ESI, MH⁺]: 178.0.

Example 81

Synthesis of Compound 5

Compound 4 (33 g, 217 mmol) and NH₂OH.HCl (45.2 g, 650.3 mmol) wereadded to EtOH (500 mL). The reaction mixture was refluxed for 16 h. Thereaction mixture was concentrated, purified by silica gel column(PE:EA=4:1), afforded compound 5 (5.2 g, 14.3%).

Synthesis of Compound 6

Compound 5 (5.2 g, 31.1 mmol) was dissolved in DMA/MeCN (6 mL/18 mL),cooled to 0° C. POCl₃ (5.2 g, 34.2 mmol) was added dropwise to keep theinner temperature below 10° C., then stirred at RT for 1 h. The reactionwas monitored by TLC. The reaction mixture was poured into crush-ice(200 mL) containing NaOAc (7.5 g, 91.4 mmol), stirred for 5 min, thenstand for 30 min. The precipitate was collected by filtration, dried,afforded compound 6 (2.9 g, 63%).

6-Hydroxy-2-methylbenzo[d]oxazole-7-carbaldehyde

Compound 6 (0.5 g, 3.3 mmol) and HMTA (1.88 g, 13.4 mmol) were added toTFA (40 mL). The mixture was heated to 70° C. for 16 h. After cooled toRT, the reaction mixture was concentrated, purified by prep-TLC,afforded 6-Hydroxy-2-methylbenzo[d]oxazole-7-carbaldehyde (40.0 mg,6.7%) as yellow solid. ¹HNMR (CDCl₃, 400 MHz): δ 11.14 (s, 1H, OH),10.41 (s, 1H, CHO), 7.77 (d, J=8.8 Hz, 1H, ArH), 6.91 (d, J=8.8 Hz, 1H,ArH), 2.66 (s, 3H, CH₃). MS [ESI, MH⁺]: 178.0.

Example 82

Synthesis of Compound 2

A mixture of compound 1 (3.0 g, 23.0 mmol) and triethyl orthoformate (50mL) was refluxed for 5 h. After cooled to RT, triethyl orthoformate wasremoved under high vacuum. The residue was purified by silica gel columnto give compound 2 (1.3 g, 38% yield) as white solid.

Synthesis of Compound 3

The solution of compound 2 (1.2 g, 8.0 mmol) in DCM (50 mL) was cooledto −60° C. The solution of BBr₃ (10.0 g, 40.0 mmol) in DCM (30 mL) wasadded dropwise keep temperature below −50° C. After stirred for another2 h at RT, the reaction mixture was quenched with MeOH at −60° C. Thereaction mixture was diluted with DCM (200 mL), and the solution waswashed with sat. NaHCO₃, brine, dried over Na₂SO₄, concentrated to givecompound 3 (0.6 g, 60% yield) as white solid. MS [ESI, MH⁺]: 136.2.

5-Hydroxybenzo[d]oxazole-4-carbaldehyde

A mixture of compound 3 (350 mg, 1.05 mmol) and HMTA (560 mg, 4 mmol) inAcOH (35 mL) was heated to 90° C. under N₂ for 1.5 h. The reaction wasmonitored by LCMS. After cooled to RT, the solvent was removed undervacuum. The residue was purified by prep-HPLC to give5-hydroxybenzo[d]oxazole-4-carbaldehyde (152 mg, 25% yield). ¹HNMR(DMSO, 400 MHz): δ 10.99 (s, 1H, OH), 10.53 (s, 1H, CHO), 8.86 (s, 1H,ArH), 8.00 (d, 1H, J=9.2 Hz, ArH), 7.05 (d, 1H, J=8.8 Hz, ArH). MS [ESI,MH⁺]: 164.1.

Example 83

Synthesis of Compound 2

A stirred mixture of rhodanine (31 g, 232 mmol), sodium acetate (1.76 g,21 mmol), compound 1 (28.2 g, 232 mmol), glacial acetic acid (5.3 mL)and toluene (300 mL) were heated to reflux for 4 hours in around-bottomed flask equipped with a Dean and Stark water separator.During this time a total of 45 mL of water was collected and a yellowprecipitate was resulted. After concentrating this mixture toapproximately half of its volume, it was cooled to 5° C. The separatedyellow solid was filtered and collected, afforded compound 2 (54.8 g,100%), without further purification, go to next step directly.

Synthesis of Compound 3

Compound 2 (54.8 g, 231 mmol) was dissolved in a solution of sodiumhydroxide (46.2 g, 1155 mmol) in water (750 mL) and kept at 60-70° C.for 30 minutes. During the last 15 minutes, it was treated with charcoaland filtered. The filtrate was cooled to 5-10° C. and acidified understirring by dropwise addition of concentrated HCl. The precipitatedsolid was collected, washed with water and dried in vacuum to givecompound 3 (38.6 g, 85.7% yield) as yellow solid.

Synthesis of Compound 4

A stirred solution of compound 3 (38.6 g, 195.94 mmol) and iodine (62.5g, 244.92 mmol) in dry THF was heated to reflux for 26 h. After removingalmost of THF, the residue was poured into water. The pH was adjusted to12 by progressively adding solid NaOH and the water phase was washedwith EA for 3 times, then the water phase was acidified by conc. HCl topH 2. The result precipitate was collected by filtration, washed bywater, dried to give compound 4 (13.5 g, 35%) as light yellow solid.

Synthesis of Compound 5

The mixture of compound 4 (1.0 eq), PyBOP (1.0 eq), amine (1.0 eq) andDIPEA (2.0 eq) were added to dry THF. The reaction mixture was stirredat RT for 16 h. The mixture was concentrated and purified by columnchromatogram to give compound 5.

Synthesis of Compound 6

A mixture of compound 5 (1.0 eq) and HMTA (4.0 eq) in TFA was heated to80° C. under nitrogen for 16 h. LC-MS indicated that the reaction wascompleted. After cooled to RT, the solvent was removed under vacuum. Theresidue was purified by prep-HPLC, afforded compound 6.

4-Formyl-5-hydroxy-N-(2-methoxyethyl)benzo[b]thiophene-2-carboxamide wasobtained by the above procedure from amine A1. 10% yield. ¹HNMR (DMSO,400 MHz): δ 11.02 (s, 1H, OH), 10.56 (s, 1H, CHO), 9.00 (t, 1H, J=5.6Hz, NH), 8.80 (d, 1H, J=0.4 Hz, ArH), 8.13 (dd, 1H, J=8.8, 0.4 Hz, ArH),7.14 (d, 1H, J=8.8 Hz, ArH), 3.48-3.40 (m, 4H, CH₂), 3.28 (s, 3H, CH₃);MS [ESI, MH⁺]: 280.1.

5-Hydroxy-2-(morpholine-4-carbonyl)benzo[b]thiophene-4-carbaldehyde wasobtained by the above procedure from amine A2. 10% yield. ¹HNMR (DMSO,400 MHz): δ 11.15 (s, 1H, —OH), 10.56 (s, 1H, CHO), 8.34 (s, 1H, ArH),8.16 (dd, 1H, J=9.2, 0.8 Hz) 7.14 (d, 1H, J=8.8 Hz, ArH), 3.64 (d, 8H,J=4.4 Hz, CH₂). MS [ESI, MH⁺]: 292.1.

5-Hydroxy-2-(4-methylpiperazine-1-carbonyl)benzo[b]thiophene-4-carbaldehydewas obtained by the above procedure from amine A3. 10% yield. ¹HNMR(DMSO, 400 MHz): δ 10.53 (s, 1H, CHO), 8.30 (s, 1H, ArH), 8.10 (d, 1H,J=8.8 Hz, ArH), 7.10 (d, 1H, J=8.8 Hz, ArH), 3.61 (t, 4H, J=4.4 Hz,CH₂), 2.32 (s, 4H, CH₂), 2.17 (s, 3H, CH₃). MS [ESI, MH⁺]: 305.2.

N-Ethyl-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxamide was obtainedby the above procedure from amine A4. 10% yield. ¹HNMR (DMSO, 400 MHz):δ 11.00 (s, 1H, OH), 10.58 (s, 1H, CHO), 8.92 (t, 1H, J=5.6 Hz, NH),8.77 (s, 1H, ArH), 8.12 (d, 1H, J=8.8 Hz, ArH), 7.14 (d, 1H, J=8.8 Hz,ArH), 3.29-3.24 (m, 2H, CH₂), 1.12 (t, 3H, J=7.2 Hz, CH₃). MS [ESI,MH⁺]: 250.1.

4-Formyl-5-hydroxy-N-(2-morpholinoethyl)benzo[b]thiophene-2-carboxamidewas obtained by the above procedure from amine A5. 10% yield. ¹HNMR(DMSO, 400 MHz): δ10.40 (s, 1H, CHO), 8.73-8.72 (m, 3H, ArH), 7.88 (d,1H, J=9.2 Hz, ArH), 6.90 (d, 1H, J=9.2 Hz, ArH), 3.53 (t, 6H, J=4.4 Hz,CH₂), 2.38 (s, 6H, CH₂). MS [ESI, MH⁺]: 335.2.

N-(2-(Dimethylamino)ethyl)-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxamidewas obtained by the above procedure from amine A6. 10% yield. ¹HNMR(DMSO, 400 MHz): δ10.54 (s, 1H, CHO), 8.84 (t, 1H, J=5.6 Hz, NH), 8.75(s, 3H, ArH), 8.09 (d, 1H, J=8.8 Hz, ArH), 7.12 (d, 1H, J=9.2 Hz, ArH),3.35-3.30 (m, 2H, CH₂), 2.44-2.41 (m, 2H, CH₂), 2.18 (s, 6H, CH₃); MS[ESI, MH⁺]: 293.2.

Example 84

Synthesis of Compound 2

To the solution of compound 1 (5 g, 0.028 mol) in EtOH (250 mL) wasadded H₂SO₄ (0.5 mL). The mixture was heated to reflux for 12 h. Aftercooled to RT, the reaction mixture was concentrated and dissolved in DCM(100 mL). The DCM layer was washed with sat. NaHCO₃, dried over Na₂SO₄,concentrated to give compound 2 (5.0 g, 86% yield) as white solid.

Synthesis of Compound 4

The mixture of compound 2 (5 g, 0.024 mol) and compound 3 (3.7 g, 0.024mol) was heated to 160-180° C. under N₂ for 2 h. After cooled to RT, thereaction mixture was dissolved in MeOH (5 mL) at 70° C. Then the mixturewas cooled to RT, the formed precipitate was filtered and washed withMeOH, dried to give compound 4 (3.0 g, 40% yield) as yellow solid.

Synthesis of Compound 5

The suspension of compound 4 (3.0 g, 9.7 mmol) in 5M HCl (100 mL) washeated at 70° C. for 2 h. After cooled to RT, the reaction mixture wasdiluted with water (50 mL), the formed precipitate was filtered andwashed with water, dried to give compound 5 (2.0 g, 90.5% yield). ¹H NMR(CDCl₃, 400 MHz): δ 11.72 (s, 1H, OH), δ 10.40 (s, 1H, CHO), 9.08 (br,1H, NH), 7.58 (d, 1H, J=9.2 Hz, ArH), 7.44 (s, 1H, ArH), 6.97 (d, 1H,J=9.2 Hz, ArH), 4.41 (q, 2H, J=7.2 Hz, CH₂), 1.41 (t, 3H, J=7.2 Hz,CH₃).

Synthesis of Compound 6

To the solution of compound 5 (2.0 g, 8.0 mmol) in MeOH (30 mL), thesolution of LiOH—H₂O (0.5 g, 12.0 mmol) in H₂O (15 mL) was added. Themixture was heated to 60° C. for 2 h. After cooled to RT, the reactionmixture was concentrated, then acidified with 3 M HCl to pH=2. Theformed precipitate was filtered and washed with water, dried to givecompound 6 (1.6 g, 91.4% yield). MS [ESI, MH⁺]: 206.1.

Synthesis of Compound 7

To the solution of compound 6 (1 eq), amine (1 eq) and PyBOP (1 eq) inDMF was added DIPEA (2 eq) dropwise at 0° C. Then the reaction mixturewas stirred at RT overnight. LCMS showed that starting material wasconsumed completed, the reaction mixture was concentrated and purifiedby prep-HPLC to give compound 7.

4-Formyl-5-hydroxy-N-(2-methoxyethyl)-1H-indole-2-carboxamide wasobtained by the above procedure from amine A1. 18% yield. ¹H NMR (MeOD,400 MHz): δ 10.45 (s, 1H, CHO), 7.60 (dd, 1H, J=0.8 Hz, J=8.8 Hz, ArH),7.47 (d, 1H, J=1.2 Hz, ArH), 6.81 (d, 1H, J=9.2 Hz, ArH), 3.53 (m, 4H,2CH₂), 3.34 (s, 3H, OCH₃);

MS [ESI, MH⁺]: 263.2.

5-Hydroxy-2-(morpholine-4-carbonyl)-1H-indole-4-carbaldehyde wasobtained by the above procedure from amine A2. 25% yield. ¹H NMR (DMSO,400 MHz): δ 11.80 (s, 1H, OH), 10.53 (s, 1H, CHO), 10.51 (s, 1H, NH),7.59 (dd, 1H, J=0.8 Hz, J=8.8 Hz, ArH), 7.26 (dd, 1H, J=0.8 Hz, ArH),6.87 (d, 1H, J=8.8 Hz, ArH), 3.73 (s, 4H, 2CH₂), 3.63 (m, 4H, 2CH₂). MS[ESI, MH⁺]: 275.2.

5-Hydroxy-2-(4-methylpiperazine-1-carbonyl)-1H-indole-4-carbaldehyde wasobtained by the above procedure from amine A3. 23.6% yield. ¹H NMR (D₂O,400 MHz): δ 9.97 (s, 1H, CHO), 7.42 (d, 1H, J=9.2 Hz, ArH), 6.91 (s, 1H,ArH), 6.63 (d, 1H, J=9.2 Hz, ArH), 4.53 (d, 2H, J=14.8 Hz, CH₂),3.55-3.41 (m, 4H), 3.09 (m, 2H, CH₂), 2.85 (s, 3H, NCH₃), MS [ESI, MH⁺]:288.2.

N-Ethyl-4-formyl-5-hydroxy-1H-indole-2-carboxamide was obtained by theabove procedure from amine A4. 30% yield. ¹H NMR (DMSO, 400 MHz): δ11.68 (s, 1H, OH), δ 10.50 (s, 1H, CHO), δ 10.32 (s, 1H, NH), 8.56 (br,1H, NH), 7.62 (d, 1H, J=1.6 Hz, ArH), 7.54 (d, 1H, J=4.8 Hz, ArH), 6.83(d, 1H, J=4.8 Hz, ArH), 3.24 (m, 2H, CH₂), 1.09 (t, 3H, J=7.2 Hz, CH₃).MS [ESI, MH⁺]: 233.2.

4-Formyl-5-hydroxy-N-(2-morpholinoethyl)-1H-indole-2-carboxamide wasobtained by the above procedure from amine A5. 22% yield. ¹H NMR (D₂O,400 MHz): δ 9.93 (s, 1H, CHO), 7.37 (d, 1H, J=8.8 Hz, ArH), 6.96 (s, 1H,ArH), 6.63 (d, 1H, J=8.8 Hz, ArH), 4.03 (d, 2H, CH₂), 3.78-3.67 (m, 4H,2CH₂), 3.56 (d, 2H, J=12.4 Hz, CH₂), 3.35 (t, 2H, J=6.0 Hz, CH₂), 3.17(t, 2H, J=11.2 Hz, CH₂). MS [ESI, MH⁺]: 318.3.

N-(2-(Dimethylamino)ethyl)-4-formyl-5-hydroxy-1H-indole-2-carboxamidewas obtained by the above procedure from amine A6. 25% yield. ¹H NMR(MeOD, 400 MHz): δ 10.49 (s, 1H, CHO), 7.64 (d, 1H, J=8.8 Hz, ArH), 7.52(s, 1H, ArH), 6.85 (d, 1H, J=8.8 Hz, ArH), 3.55 (t, 2H, J=6.4 Hz, CH₂),2.64 (t, 2H, J=6.4 Hz, CH₂), 2.36 (s, 6H, 2NCH₃). MS [ESI, MH⁺]: 276.2.

Example 85

Synthesis of Compound 3

The mixture of compound 1 (15.2 g, 0.1 mol), compound 2 (16.6 g, 0.1mol) and K₂CO₃ (27.6 g, 0.2 mol) in DMF (150 mL) was heated to refluxunder N₂ for 2 h. After cooled to RT, the reaction mixture wasconcentrated and dissolved in DCM (100 mL), the solution washed withsat. NaHCO₃, brine, dried over Na₂SO₄, concentrated. The residue waspurified by silica gel column to give compound 3 (11.8 g, 62% yield) aswhite solid.

Synthesis of Compound 4

The solution of BBr₃ (40 g, 160.0 mmol) in DCM (100 mL) was addeddropwise to the solution of compound 3 (9g, 40.9 mmol) in DCM (300 mL)at −60° C. After that the reaction mixture was warmed slowly to 0° C.and stirred for another 1 h. The reaction mixture was quenched with EtOH(10 ml) slowly at −60° C. The reaction mixture was washed with water,brine, dried over Na₂SO₄, concentrated to give compound 4 (8.8 g, 100%yield). MS [ESI, MH⁺]: 206.1.

Ethyl 4-formyl-5-hydroxybenzofuran-2-carboxylate

The mixture of compound 4 (5.0 g, 24.3 mmol), and HMTA (13.5 g, 97.0mmol) in TFA (500 mL) was heated to 100° C. under N₂ for 2 h. Thereaction was monitored by LCMS. The reaction mixture was concentrated,diluted with H₂O (20 mL) and stirred for 30 min. The formed precipitatewas filtered, washed with water, dried to give MNKD-227 (3.0 g, 53.5%yield). ¹HNMR (CDCl₃, 400 MHz): δ 11.45 (s, 1H, OH), 10.26 (d, 1H, J=0.4Hz, CHO), 7.72 (s, 1H, ArH), 7.68 (d, 1H, J=9.2 Hz, ArH), 7.02 (d, 1H,J=9.2 Hz, ArH), 4.40 (q, 2H, J=7.2 Hz, CH₂), 1.37 (t, 3H, J=7.2 Hz,CH₃). MS [ESI, MH⁺]: 235.1.

4-Formyl-5-hydroxybenzofuran-2-carboxylic acid

The solution of LiOH—H₂O (1.26 g, 60 mmol) in H₂O (15 mL) was addeddropwise to the solution of ethyl4-formyl-5-hydroxybenzofuran-2-carboxylate (4.6 g, 20 mmol) in THF (40mL). The reaction mixture was heated to 50° C. for 2 h. After cooled toRT, the reaction mixture was concentrated, then acidified with 3 M HClto pH=2. The formed precipitate was filtered and washed with water,dried to give 4-formyl-5-hydroxybenzofuran-2-carboxylic acid (4.1 g.87.8% yield). ¹HNMR (DMSO, 400 MHz): δ 10.91 (s, 1H, OH), 10.47 (s, 1H,CHO), 7.92 (d, 1H, J=0.8 Hz, ArH), 7.87 (dd, 1H, J=9.2 Hz, 0.8 Hz, ArH),7.13 (d, 1H, J=9.2 Hz, ArH); MS [ESI, MH⁺]: 207.1.

Synthesis of Compound 5

To the solution of 4-formyl-5-hydroxybenzofuran-2-carboxylic acid (1eq), amine (1 eq) and PyBOP (1 eq) in DMF was added DIPEA (2 eq)dropwise keeping the inner temperature below 10° C. The reaction mixturewas stirred at RT for 2 h. The reaction was monitored by LCMS. Thereaction mixture was concentrated and purified by prep-HPLC to givecompound 5.

4-Formyl-5-hydroxy-N-(2-methoxyethyl)benzofuran-2-carboxamide wasobtained by the above procedure from amine A1. 17.6% yield. ¹HNMR (DMSO,400 MHz): δ 10.80 (s, 1H, OH), 10.47 (s, 1H, CHO), 8.77 (t, 1H, J=5.2Hz, NH), 7.96 (d, 1H, J=0.8 Hz, ArH), 7.81 (dd, 1H, J=8.8 Hz, 0.8 Hz,ArH), 7.06 (d, 1H, J=8.8 Hz, ArH), 3.41 (m, 4H, 2CH₂), 3.24 (s, 3H,OCH₃). MS [ESI, MH⁺]: 264.1.

5-Hydroxy-2-(morpholine-4-carbonyl)benzofuran-4-carbaldehyde wasobtained by the above procedure from amine A2. 21.7% yield. ¹HNMR(CDCl3, 400 MHz): δ 11.48 (s, 1H, OH), 10.31 (s, 1H, CHO), 7.65 (d, 1H,J=1.2 Hz, ArH), 7.03 (d, 1H, J=9.2 Hz, ArH), 3.87-3.78 (m, 8H); MS [ESI,MH⁺]: 276.2.

5-Hydroxy-2-(4-methylpiperazine-1-carbonyl)benzofuran-4-carbaldehyde wasobtained by the above procedure from amine A3. 30% yield. ¹HNMR (MeOD,400 MHz): δ 7.63 (s, 1H, ArH), 7.41 (d, 1H, J=9.2 Hz, ArH), 6.97 (dd,1H, J=8.8 Hz, 0.8 Hz, ArH), 5.87 (d, 1H, J=0.8 Hz, NH), 4.79 (d. 2H,J=14.8 Hz, CH₂), 3.63-3.48 (m, 4H, 2CH₂), 3.25-3.22 (m. 2H, CH₂), 2.96(s, 3H, CH₃); MS [ESI, MH⁺]: 289.2.

N-Ethyl-4-formyl-5-hydroxybenzofuran-2-carboxamide was obtained by theabove procedure from amine A4. 18.7% yield. ¹HNMR (DMSO, 400 MHz): δ10.80 (s, 1H, OH), 10.47 (s, 1H, CHO), 8.77 (t, 1H, J=5.2 Hz, NH), 7.94(s, 1H, ArH), 7.80 (dd, 1H, J=8.8 Hz, 0.8 Hz, ArH), 7.08 (d, 1H, J=8.8Hz, ArH), 3.26 (m, 2H, CH₂), 1.10 (t, 3H, J=7.2 Hz, CH₃); MS [ESI, MH⁺]:234.2.

4-Formyl-5-hydroxy-N-(2-morpholinoethyl)benzofuran-2-carboxamide wasobtained by the above procedure from amine A5. 21.7% yield. ¹HNMR (MeOD,400 MHz): δ 7.72 (d, 1H, J=1.2 Hz, ArH), 7.40 (dd, 1H, J=8.8 Hz, 1.2 Hz,ArH), 6.97 (d, 1H, J=8.8 Hz, ArH), 5.87 (s, 1H, NH), 4.08 (m. 2H, CH₂),3.80 (t, 4H, J=5.6 Hz, 2CH₂), 3.68 (d. 2H, J=12.0 Hz, CH₂), 3.25-3.17(m, 2H, CH₂); MS [ESI, MH⁺]: 319.2.

N-(2-(dimethylamino)ethyl)-4-formyl-5-hydroxybenzofuran-2-carboxamidewas obtained by the above procedure from amine A6. 25% yield. ¹HNMR(DMSO, 400 MHz): δ 10.89 (s, 1H, OH), 10.48 (s, 1H, CHO), 9.41 (br, 1H,NH), 8.97 (br, 1H, NH), 7.98 (s, 1H, ArH), 7.84 (d, 1H, J=8.8 Hz, ArH),7.12 (d, 1H, J=9.2 Hz, ArH), 3.59 (d, 2H, J=6.4 Hz, CH₂), 3.24 (s, 2H,CH₂), 2.81 (s, 6H, 2CH₃); MS [ESI, MH⁺]: 277.2.

The invention claimed is:
 1. A compound of formula (A-1k):

or a pharmaceutically acceptable salt thereof; wherein R3 is hydrogen,optionally substituted alkoxyl, or optionally substituted alkylamino; R4is hydrogen or alkoxyl; R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF₃,or, together with R6 and the carbon atoms to which they are attached,forms a five-membered cycloalkyl; R6 is (a) alkenyl, optionallysubstituted with 1-3 substituents selected from halogen, —CN, alkyl,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,

 or (b) alkyl, substituted with 1-3 substituents selected from halogen,—CN, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,perfluoroalkoxy,

 or (c) phenyl, substituted with 1-3 substituents selected from halogen,—CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl,perfluoroalkoxy,

R9 and R10 are independently hydrogen; alkyl; alkoxylalkyl;perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3substituents independently selected from R21; a 5- or 6-memberedheterocycle, optionally substituted with 1, 2, or 3 substituentsindependently selected from R21; a 5- or 6-membered heteroaryl,optionally substituted with 1, 2, or 3 substituents independentlyselected from R21; or

wherein n is 0, 1, 2, or 3; or R9 and R10, together with the nitrogenatom to which they are attached, form a heterocycle containing 1, 2, 3,or 4 heteroatoms selected from N, O, and S, optionally substituted with1, 2, or 3 substituents selected independently from R11; R11 ishydrogen; alkyl; aryl; heteroaryl containing 1 or 2 heteroatoms selectedfrom N, O, and S; arylalkyl; heteroarylalkyl in which the heteroarylcontains 1 or 2 heteroatoms selected from N, O, and S;

R12 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3substitutents selected independently from R11; a 5- or 6-memberedheterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S andoptionally substituted with 1, 2, or 3 substitutents selectedindependently from R11; or a 5- or 6-membered heteroaryl having 1, 2, or3 heteroatoms selected from N, O, and S and optionally substituted with1, 2, or 3 substitutents selected independently from R11; R13 is alkyl;alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally substituted with1, 2, or 3 substituents independently selected from R21; a 5- or6-membered heterocycle, optionally substituted with 1, 2, or 3substituents independently selected from R21; a 5- or 6-memberedheteroaryl, optionally substituted with 1, 2, or 3 substituentsindependently selected from R21; or

wherein n is 0, 1, 2, or 3; and R14 is hydrogen or R13; or R13 and R14,together with the nitrogen to which they are attached, form aheterocycle containing 1, 2, or 3 heteroatoms selected independentlyfrom N, O, and S, optionally substituted with 1, 2, or 3 substitutentsselected independently from R16; R15 is amino; alkoxy; aryl, optionallysubstituted with 1, 2, or 3 substitutents selected independently fromR21; a 5- or 6-membered heterocycle having 1, 2, or 3 heteroatomsselected from N, O, and S and optionally substituted with 1, 2, or 3substitutents selected from R21; or a 5- or 6-membered heteroaryl having1, 2, or 3 heteroatoms selected from N, O, and S and optionallysubstituted with 1, 2, or 3 substitutents selected from R21; R16 ishydrogen; alkyl; aryl; heteroaryl containing 1 or 2 heteroatoms selectedfrom N, O, and S; arylalkyl; heteroarylalkyl in which the heteroarylcontains 1 or 2 heteroatoms selected from N, O, and S;

amino; or

R17 is alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionallysubstituted with 1, 2, or 3 substituents independently selected fromR21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2,or 3 substituents independently selected from R21; a 5- or 6-memberedheteroaryl, optionally substituted with 1, 2, or 3 substituentsindependently selected from R21; or

wherein n is 0, 1, 2, or 3; and R18 is hydrogen or R17; or R17 and R18,together with the nitrogen to which they are attached, form aheterocycle containing 1, 2, 3, or 4 heteroatoms selected independentlyfrom N, O, and S, optionally substituted with 1, 2, or 3 substituentsselected independently from R20; R19 is alkoxy; aryl, optionallysubstituted with 1, 2, or 3 substitutents selected independently fromR21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2,or 3 substituents independently selected from R21; or a 5- or 6-memberedheteroaryl, optionally substituted with 1, 2, or 3 substituentsindependently selected from R21; R20 is a 5- or 6-membered heterocyclehaving 1 or 2 heteroatoms selected from N, O, and S and optionallysubstituted with 1, 2, or 3 substituents selected independently fromR21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or3 substituents selected independently from R21; or R21; and R21 ishalogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH₂, —CON(CH₃)₂,alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl, wherein the compounddirectly inhibits IRE-1α activity in vitro.
 2. A pharmaceuticalcomposition comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable vehicle. 3.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R3 is optionally substituted alkoxyl.
 4. The compound of claim 1or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.5. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R5 is alkyl.
 6. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R6 is alkyl,substituted with 1-3 substituents selected from halogen, —CN,perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,


7. The compound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 8. The pharmaceuticalcomposition of claim 2, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 10. The pharmaceuticalcomposition of claim 2, wherein the compound is

or a pharmaceutically acceptable salt thereof.